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Bhat V, Piaseczny M, Goodale D, Patel U, Sadri A, Allan AL. Lung-derived soluble factors support stemness/plasticity and metastatic behaviour of breast cancer cells via the FGF2-DACH1 axis. Clin Exp Metastasis 2024; 41:717-731. [PMID: 38581619 PMCID: PMC11499378 DOI: 10.1007/s10585-024-10284-4] [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: 10/14/2023] [Accepted: 03/20/2024] [Indexed: 04/08/2024]
Abstract
Patients with triple-negative breast cancer (TNBC) have an increased propensity to develop lung metastasis. Our previous studies demonstrated that stem-like ALDHhiCD44+ breast cancer cells interact with lung-derived soluble factors, resulting in enhanced migration and lung metastasis particularly in TNBC models. We have also observed that the presence of a primary TNBC tumor can 'prime' the lung microenvironment in preparation for metastasis. In this study, we hypothesized that soluble lung-derived factors secreted in the presence of a primary TNBC tumor can influence stemness/plasticity of breast cancer cells. Using an ex vivo pulmonary metastasis assay (PuMA), we observed that the lung microenvironment supports colonization and growth of ALDHhiCD44+ TNBC cells, potentially via interactions with lung-derived FGF2. Exposure of TNBC cells to lung-conditioned media (LCM) generated from mice bearing TNBC primary tumors (tbLCM) significantly enhanced the proportion of ALDHhiCD44+ cells compared to control or LCM from tumor-naïve mice (tnLCM). Further analysis using a human cancer stem cell qPCR array revealed that, relative to tnLCM or control, exposure of TNBC cells to tbLCM leads to downregulation of the transcription factor and putative tumor suppressor Dachshund homolog 1 (DACH1), a downstream regulator of FGF2. In addition, inhibition of DACH1 using siRNA or treatment with recombinant FGF2 enhanced the ALDHhiCD44+ phenotype. Taken together, our findings suggest that the FGF2-DACH1 signaling axis supports stemness/plasticity of TNBC cells in the lung microenvironment and lays the foundation for future evaluation of FGF2 as a potential novel therapeutic target for treatment or prevention of breast cancer metastasis to the lung.
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Affiliation(s)
- Vasudeva Bhat
- London Regional Cancer Program, London Health Science Centre, London, ON, N6A 5W9, Canada.
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada.
| | - Matthew Piaseczny
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada
| | - David Goodale
- London Regional Cancer Program, London Health Science Centre, London, ON, N6A 5W9, Canada
| | - Urvi Patel
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada
| | - Ashkan Sadri
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada
| | - Alison L Allan
- London Regional Cancer Program, London Health Science Centre, London, ON, N6A 5W9, Canada
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5C1, Canada
- Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, ON, N6A 5W9, Canada
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Zeng P, Shu LZ, Zhou YH, Huang HL, Wei SH, Liu WJ, Deng H. Stem Cell Division and Its Critical Role in Mammary Gland Development and Tumorigenesis: Current Progress and Remaining Challenges. Stem Cells Dev 2024; 33:449-467. [PMID: 38943275 DOI: 10.1089/scd.2024.0035] [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] [Indexed: 07/01/2024] Open
Abstract
The origin of breast cancer (BC) has traditionally been a focus of medical research. It is widely acknowledged that BC originates from immortal mammary stem cells and that these stem cells participate in two division modes: symmetric cell division (SCD) and asymmetrical cell division (ACD). Although both of these modes are key to the process of breast development and their imbalance is closely associated with the onset of BC, the molecular mechanisms underlying these phenomena deserve in-depth exploration. In this review, we first outline the molecular mechanisms governing ACD/SCD and analyze the role of ACD/SCD in various stages of breast development. We describe that the changes in telomerase activity, the role of polar proteins, and the stimulation of ovarian hormones subsequently lead to two distinct consequences: breast development or carcinogenesis. Finally, gene mutations, abnormalities in polar proteins, modulation of signal-transduction pathways, and alterations in the microenvironment disrupt the balance of BC stem cell division modes and cause BC. Important regulatory factors such as mammalian Inscuteable mInsc, Numb, Eya1, PKCα, PKCθ, p53, and IL-6 also play significant roles in regulating pathways of ACD/SCD and may constitute key targets for future research on stem cell division, breast development, and tumor therapy.
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MESH Headings
- Humans
- Female
- Breast Neoplasms/pathology
- Breast Neoplasms/metabolism
- Breast Neoplasms/genetics
- Animals
- Mammary Glands, Human/growth & development
- Mammary Glands, Human/pathology
- Mammary Glands, Human/cytology
- Mammary Glands, Human/metabolism
- Carcinogenesis/pathology
- Carcinogenesis/metabolism
- Carcinogenesis/genetics
- Stem Cells/metabolism
- Stem Cells/cytology
- Cell Division
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Mammary Glands, Animal/growth & development
- Mammary Glands, Animal/cytology
- Mammary Glands, Animal/pathology
- Mammary Glands, Animal/metabolism
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Signal Transduction
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Affiliation(s)
- Peng Zeng
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Lin-Zhen Shu
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yu-Hong Zhou
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Hai-Lin Huang
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Shu-Hua Wei
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Wen-Jian Liu
- Department of Breast Surgery, Jiangxi Armed Police Corps Hospital, Nanchang, China
| | - Huan Deng
- Affiliated Rehabilitation Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- The Fourth Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
- Tumor Immunology Institute, Nanchang University, Nanchang, China
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, China
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Zhang X, Niu M, Li T, Wu Y, Gao J, Yi M, Wu K. S100A8/A9 as a risk factor for breast cancer negatively regulated by DACH1. Biomark Res 2023; 11:106. [PMID: 38093319 PMCID: PMC10720252 DOI: 10.1186/s40364-023-00548-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 12/02/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND S100A8 and S100A9 are members of Ca2+-binding EF-hand superfamily, mainly expressed by macrophages and neutrophils. Limited by the poor stability of homodimers, they commonly exist as heterodimers. Beyond acting as antibacterial cytokines, S100A8/A9 is also associated with metabolic and autoimmune diseases such as obesity, diabetes, and rheumatoid arthritis. While the involvement of S100A8/A9 in breast cancer development has been documented, its prognostic significance and the precise regulatory mechanisms remain unclear. METHODS S100A8/A9 protein in breast cancer samples was evaluated by immunohistochemistry staining with tumor tissue microarrays. The serum S100A8 concentration in patients was measured by enzyme-linked immunosorbent assay (ELISA). The S100A8 secreted by breast cancer cells was detected by ELISA as well. Pooled analyses were conducted to explore the relationships between S100A8/A9 mRNA level and clinicopathological features of breast cancer patients. Besides, the effects of S100A8/A9 and DACH1 on patient outcomes were analyzed by tissue assays. Finally, xenograft tumor assays were adopted to validate the effects of DACH1 on tumor growth and S100A8/A9 expression. RESULTS The level of S100A8/A9 was higher in breast cancer, relative to normal tissue. Increased S100A8/A9 was related to poor differentiation grade, loss of hormone receptors, and Her2 positive. Moreover, elevated S100A8/A9 predicted a worse prognosis for breast cancer patients. Meanwhile, serum S100A8 concentration was upregulated in Grade 3, basal-like, and Her2-overexpressed subtypes. Additionally, the results of public databases showed S100A8/A9 mRNA level was negatively correlated to DACH1. Stable overexpressing DACH1 in breast cancer cells significantly decreased the generation of S100A8. The survival analysis demonstrated that patients with high S100A8/A9 and low DACH1 achieved the shortest overall survival. The xenograft models indicated that DACH1 expression significantly retarded tumor growth and downregulated S100A8/A9 protein abundance. CONCLUSION S100A8/A9 is remarkedly increased in basal-like and Her2-overexpressed subtypes, predicting poor prognosis of breast cancer patients. Tumor suppressor DACH1 inhibits S100A8/A9 expression. The combination of S100A8/A9 and DACH1 predicted the overall survival of breast cancer patients more preciously.
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Affiliation(s)
- Xiaojun Zhang
- General Surgery Department, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi HospitalThird Hospital of Shanxi Medical University, Taiyuan, China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yuze Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinnan Gao
- General Surgery Department, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi HospitalThird Hospital of Shanxi Medical University, Taiyuan, China
| | - Ming Yi
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
| | - Kongming Wu
- General Surgery Department, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi HospitalThird Hospital of Shanxi Medical University, Taiyuan, China.
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Miziak P, Baran M, Błaszczak E, Przybyszewska-Podstawka A, Kałafut J, Smok-Kalwat J, Dmoszyńska-Graniczka M, Kiełbus M, Stepulak A. Estrogen Receptor Signaling in Breast Cancer. Cancers (Basel) 2023; 15:4689. [PMID: 37835383 PMCID: PMC10572081 DOI: 10.3390/cancers15194689] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors necessary for cancer invasion and dissemination. The significance of the clinical implications of ER signaling in BC, including the potential of endocrine therapies that target estrogens' synthesis and ER-dependent signal transmission, such as aromatase inhibitors or selective estrogen receptor modulators, is discussed. As a consequence, the challenges associated with the resistance to these therapies resulting from acquired ER mutations and potential strategies to overcome them are the critical point for the new treatment strategies' development.
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Affiliation(s)
- Paulina Miziak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Marzena Baran
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Ewa Błaszczak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Alicja Przybyszewska-Podstawka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Joanna Kałafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Jolanta Smok-Kalwat
- Department of Clinical Oncology, Holy Cross Cancer Centre, 3 Artwinskiego Street, 25-734 Kielce, Poland;
| | - Magdalena Dmoszyńska-Graniczka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Michał Kiełbus
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
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Zhu S, Li W, Zhang H, Yan Y, Mei Q, Wu K. Retinal determination gene networks: from biological functions to therapeutic strategies. Biomark Res 2023; 11:18. [PMID: 36750914 PMCID: PMC9906957 DOI: 10.1186/s40364-023-00459-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/28/2023] [Indexed: 02/09/2023] Open
Abstract
The retinal determinant gene network (RDGN), originally discovered as a critical determinator in Drosophila eye specification, has become an important regulatory network in tumorigenesis and progression, as well as organogenesis. This network is not only associated with malignant biological behaviors of tumors, such as proliferation, and invasion, but also regulates the development of multiple mammalian organs. Three members of this conservative network have been extensively investigated, including DACH, SIX, and EYA. Dysregulated RDGN signaling is associated with the initiation and progression of tumors. In recent years, it has been found that the members of this network can be used as prognostic markers for cancer patients. Moreover, they are considered to be potential therapeutic targets for cancer. Here, we summarize the research progress of RDGN members from biological functions to signaling transduction, especially emphasizing their effects on tumors. Additionally, we discuss the roles of RDGN members in the development of organs and tissue as well as their correlations with the pathogenesis of chronic kidney disease and coronary heart disease. By summarizing the roles of RDGN members in human diseases, we hope to promote future investigations into RDGN and provide potential therapeutic strategies for patients.
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Affiliation(s)
- Shuangli Zhu
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Wanling Li
- grid.412793.a0000 0004 1799 5032Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China ,grid.470966.aCancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032 China
| | - Hao Zhang
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Yuheng Yan
- grid.412793.a0000 0004 1799 5032Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qi Mei
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China. .,Cancer Center, Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Guchhait KC, Manna T, Barai M, Karmakar M, Nandi SK, Jana D, Dey A, Panda S, Raul P, Patra A, Bhattacharya R, Chatterjee S, Panda AK, Ghosh C. Antibiofilm and anticancer activities of unripe and ripe Azadirachta indica (neem) seed extracts. BMC Complement Med Ther 2022; 22:42. [PMID: 35152903 PMCID: PMC8843028 DOI: 10.1186/s12906-022-03513-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 01/07/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Antibiotic resistances of pathogens and breast cancer warrant the search for new alternative strategies. Phytoextracts can eradicate microbe-borne diseases as well as cancer with lower side effects compared to conventional antibiotics. AIM Unripe and ripe Azadirachta indica (neem) seed extracts were explored as potential antibiofilm and anticancer agents in combating multidrug-resistant infectious bacteria as well as anticancer agents against the MDR breast cancer cell lines. METHODS Shed-dried neem seeds (both unripe and ripe) were pulverized and extracted using methanol. The chemical components were identified with FTIR and gas chromatography - mass spectrometry. Antibiofilm activity of neem seed extracts were assessed in terms of minimum biofilm inhibitory concentration (MBIC), minimum biofilm eradication concentration (MBEC), and fluorescence microscopic studies on Staphylococcus aureus and Vibrio cholerae. Bacterial cells were studied by fluorescence microscopy using acridine orange/ethidium bromide as the staining agents. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were evaluated to observe the antibacterial activities. Cytotoxicity of the extracts against human blood lymphocytes and the anticancer activity against drug-resistant breast cancer cell lines were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and fluorescence-activated cell sorting (FACS) studies. RESULTS 4-Ethyl-2-hydroxy-2-cyclopentene-1-one, phthalic acid, and 2-hexyl-tetrahydro thiophane were the major compounds in unripe neem seed, whereas 3,5-dihydroxy-6-methyl-2,3-dihydro-4-H-pyran-4-one and 4-ethylbenzamide were predominant in ripe neem seed. Triazine derivatives were also common for both the extracts. MBIC values of unripe and ripe neem seed extracts for S. aureus are 75 and 100 µg/mL, respectively, and for V. cholerae, they are 100 and 300 µg/mL, respectively. MBEC values of unripe and ripe seed extracts are 500 and 300 µg/mL, respectively for S. aureus and for V. cholerae the values are 700 and 500 µg/mL, respectively. Fluorescence microscopic studies at 16 and 24 h, after bacterial culture, demonstrate enhanced antibiofilm activity for the ripe seed extract than that of the unripe seeds for both the bacteria. MTT assay reveals lower cytotoxicity of both the extracts towards normal blood lymphocytes, and anticancer activity against breast cancer cell line (MDA-MB-231) with superior activity of ripe seed extract. FACS studies further supported higher anticancer activity for ripe seed extract. CONCLUSIONS Methanolic extract of neem seeds could substantially inhibit and eradicate biofilm along with their potent antibacterial and anticancer activities. Both the extracts showed higher antibiofilm and antibacterial activity against S. aureus (gram-positive) than V. cholerae (gram-negative). Moreover, ripe seed extract showed higher antibiofilm and anticancer activity than unripe extracts.
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Affiliation(s)
- Kartik Chandra Guchhait
- Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Tuhin Manna
- Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Manas Barai
- Department of Chemistry, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Monalisha Karmakar
- Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Sourav Kumar Nandi
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, 3081 Nayabad, Kolkata, 700094, West Bengal, India
| | - Debarati Jana
- Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Aditi Dey
- Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Suman Panda
- Department of Biophysics, Bose Institute, P-1/12 CIT Road, Scheme VIIM, Kankurgachi, Kolkata, 700054, West Bengal, India
| | - Priyanka Raul
- Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Anuttam Patra
- Chemistry of Interfaces Group, Luleå University of Technology, SE- 97187, Luleå, Sweden
| | - Rittwika Bhattacharya
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, 3081 Nayabad, Kolkata, 700094, West Bengal, India
| | - Subhrangsu Chatterjee
- Department of Biophysics, Bose Institute, P-1/12 CIT Road, Scheme VIIM, Kankurgachi, Kolkata, 700054, West Bengal, India
| | - Amiya Kumar Panda
- Department of Chemistry, Vidyasagar University, Midnapore, 721102, West Bengal, India
- Sadhu Ram Chand Murmu University of Jhargram, Jhargram, 721507, West Bengal, India
| | - Chandradipa Ghosh
- Department of Human Physiology, Vidyasagar University, Midnapore, 721102, West Bengal, India.
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Dey A, Kundu M, Das S, Jena BC, Mandal M. Understanding the function and regulation of Sox2 for its therapeutic potential in breast cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188692. [PMID: 35122882 DOI: 10.1016/j.bbcan.2022.188692] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/11/2022] [Accepted: 01/28/2022] [Indexed: 12/12/2022]
Abstract
Sox family of transcriptional factors play essential functions in development and are implicated in multiple clinical disorders, including cancer. Sox2 being their most prominent member and performing a critical role in reprogramming differentiated adult cells to an embryonic phenotype is frequently upregulated in multiple cancers. High Sox2 levels are detected in breast tumor tissues and correlate with a worse prognosis. In addition, Sox2 expression is connected with resistance to conventional anticancer therapy. Together, it can be said that inhibiting Sox2 expression can reduce the malignant features associated with breast cancer, including invasion, migration, proliferation, stemness, and chemoresistance. This review highlights the critical roles played by the Sox gene family members in initiating or suppressing breast tumor development, while primarily focusing on Sox2 and its role in breast tumor initiation, maintenance, and progression, elucidates the probable mechanisms that control its activity, and puts forward potential therapeutic strategies to inhibit its expression.
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Affiliation(s)
- Ankita Dey
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Moumita Kundu
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Subhayan Das
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Bikash Chandra Jena
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
| | - Mahitosh Mandal
- Cancer Biology Lab, School of Medical Science and Technology, Indian Institute of Technology Kharagpur (IIT Kharagpur), Kharagpur, West Bengal, India..
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The Function of circRNA-0047604 in Regulating the Tumor Suppressor Gene DACH1 in Breast Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6589651. [PMID: 35097124 PMCID: PMC8794664 DOI: 10.1155/2022/6589651] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 12/17/2022]
Abstract
Breast cancer is the most common cancer among females. Dachshund Homolog 1 (DACH1) gene is regarded as an important tumor suppressor gene in breast cancer which plays an important regulatory role in the development disease progression, particularly in carcinomas. Circular RNAs (circRNAs) and microRNA (miRNA), regarded as a novel group of noncoding RNAs, are always involved in regulating gene expression. In this work, hsa_circ_0047604 expressed lower in breast cancer tissue and played the role of sponge of miR-548o. By this way, hsa_circ_0047604 could upregulate DACH1 to inhibit breast cancer. In conclusion, this study revealed that hsa_circ_0047604 acted as a tumor suppressor and regulated breast cancer progression via hsa_circ_0047604–miR-548o–DACH1 axis, which might provide a therapeutic method for breast cancer.
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Shintani A, Fukai S, Nobusawa R, Taniguchi K, Hatatani T, Nagai H, Sakai T, Yoshimura T, Miyasaka M, Hayasaka H. Dach1 transcription factor regulates the expression of peripheral node addressin and lymphocyte trafficking in lymph nodes. CURRENT RESEARCH IN IMMUNOLOGY 2022; 3:175-185. [PMID: 36045707 PMCID: PMC9421177 DOI: 10.1016/j.crimmu.2022.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 12/01/2022] Open
Abstract
Lymphocytes regulate the immune response by circulating between the vascular and lymphatic systems. High endothelial venules, HEVs, special blood vessels expressing selective adhesion molecules, such as PNAd and MAdCAM-1, mediate naïve lymphocyte migration from the vasculature into the lymph nodes and Peyer's patches. We have identified that DACH1 is abundantly expressed in developing HEV-type endothelial cells. DACH1 showed a restricted expression pattern in lymph node blood vessels during the late fetal and early neonatal periods, corresponding to HEV development. The proportion of MAdCAM-1+ and CD34+ endothelial cells is reduced in the lymph nodes of neonatal conventional and vascular-specific Dach1-deficient mice. Dach1-deficient lymph nodes in adult mice demonstrated a lower proportion of PNAd+ cells and lower recruitment of intravenously administered lymphocytes from GFP transgenic mice. These findings suggest that DACH1 promotes the expression of HEV-selective adhesion molecules and mediates lymphocyte trafficking across HEVs into lymph nodes.
The high endothelial venules, HEVs, develop in a tissue-specific manner and permit lymphocyte trafficking. The transcription factor DACH1 exhibit a restricted expression pattern in the blood vessels of developing lymph nodes. The blood vessel-specific Dach1-deficient lymph nodes exhibit a reduced proportion of HEVs and lymphocyte recruitment.
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Salinas-Jazmín N, Rosas-Cruz A, Velasco-Velázquez M. Reporter gene systems for the identification and characterization of cancer stem cells. World J Stem Cells 2021; 13:861-876. [PMID: 34367481 PMCID: PMC8316869 DOI: 10.4252/wjsc.v13.i7.861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/19/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) are tumor cells that share functional characteristics with normal and embryonic stem cells. CSCs have increased tumor-initiating capacity and metastatic potential and lower sensitivity to chemo- and radiotherapy, with important roles in tumor progression and the response to therapy. Thus, a current goal of cancer research is to eliminate CSCs, necessitating an adequate phenotypic and functional characterization of CSCs. Strategies have been developed to identify, enrich, and track CSCs, many of which distinguish CSCs by evaluating the expression of surface markers, the initiation of specific signaling pathways, and the activation of master transcription factors that control stemness in normal cells. We review and discuss the use of reporter gene systems for identifying CSCs. Reporters that are under the control of aldehyde dehydrogenase 1A1, CD133, Notch, Nanog homeobox, Sex-determining region Y-box 2, and POU class 5 homeobox can be used to identify CSCs in many tumor types, track cells in real time, and screen for drugs. Thus, reporter gene systems, in combination with in vitro and in vivo functional assays, can assess changes in the CSCs pool. We present relevant examples of these systems in the evaluation of experimental CSCs-targeting therapeutics, demonstrating their value in CSCs research.
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Affiliation(s)
- Nohemí Salinas-Jazmín
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Arely Rosas-Cruz
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Marco Velasco-Velázquez
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico.
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11
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Kim SH, Hahm ER, Singh KB, Singh SV. Novel mechanistic targets of forkhead box Q1 transcription factor in human breast cancer cells. Mol Carcinog 2020; 59:1116-1128. [PMID: 32754922 DOI: 10.1002/mc.23241] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 01/06/2023]
Abstract
The transcription factor forkhead box Q1 (FoxQ1) is overexpressed in different solid tumors including breast cancer, but the mechanism underlying its oncogenic function is still not fully understood. In this study, we compared RNA-seq data from FoxQ1 overexpressing SUM159 cells with that of empty vector-transfected control cells to identify novel mechanistic targets of this transcription factor. Analysis of The Cancer Genome Atlas (TCGA) data set revealed significantly higher expression of FoxQ1 in black breast cancer patients compared with white women with this disease. In contrast, expression of FoxQ1 was comparable in ductal and lobular carcinomas in the breast cancer TCGA data set. Complementing our published findings in basal-like subtype, immunohistochemistry revealed upregulation of FoxQ1 protein in luminal-type human breast cancer tissue microarrays when compared with normal mammary tissues. Many previously reported transcriptional targets of FoxQ1 (eg, E-cadherin, N-cadherin, fibronectin 1, etc) were verified from the RNA-seq analysis. FoxQ1 overexpression resulted in the downregulation of genes associated with cell cycle checkpoints, M phase, and cellular response to stress/external stimuli as evidenced from the Reactome pathway analysis. Consequently, FoxQ1 overexpression resulted in mitotic arrest in basal-like SUM159 and human mammary epithelial cell line, but not in luminal-type MCF-7 cells. Finally, we show for the first time that FoxQ1 is a direct transcriptional regulator of interleukin (IL)-1α, IL-8, and vascular endothelial growth factor in breast cancer cells as evidenced by chromatin immunoprecipitation assay. In conclusion, the present study reports novel mechanistic targets of FoxQ1 in human breast cancer cells.
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Affiliation(s)
- Su-Hyeong Kim
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Eun-Ryeong Hahm
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Krishna B Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shivendra V Singh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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12
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Dong B, Yi M, Luo S, Li A, Wu K. RDGN-based predictive model for the prognosis of breast cancer. Exp Hematol Oncol 2020; 9:13. [PMID: 32550045 PMCID: PMC7294607 DOI: 10.1186/s40164-020-00169-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/04/2020] [Indexed: 12/27/2022] Open
Abstract
Background Breast cancer is the most diagnosed malignancy in females in the United States. The members of retinal determination gene network (RDGN) including DACH, EYA, as well as SIX families participate in the proliferation, apoptosis, and metastasis of multiple tumors including breast cancer. A comprehensive predictive model of RDGN might be helpful to herald the prognosis of breast cancer patients. Methods In this study, the Gene Expression Ominibus (GEO) and Gene Set Expression Analysis (GSEA) algorithm were used to investigate the effect of RDGN members on downstream signaling pathways. Besides, based on The Cancer Genome Atlas (TCGA) database, we explored the expression patterns of RDGN members in tumors, normal tissues, and different breast cancer subtypes. Moreover, we estimated the relationship between RDGN members and the outcomes of breast cancer patients. Lastly, we constructed a RDGN-based predictive model by Cox proportional hazard regression and verified the model in two separate GEO datasets. Results The results of GSEA showed that the expression of DACH1 was negatively correlated with cell cycle and DNA replication pathways. On the contrary, the levels of EYA2 and SIX1 were significantly positively correlated with DNA replication, mTOR, and Wnt pathways. Further investigation in TCGA database indicated that DACH1 expression was lower in breast cancers especially basal-like subtype. In the meanwhile, SIX1 was remarkably upregulated in breast cancers while EYA2 level was increased in Basal-like and Her-2 enriched subtypes. Survival analyses demonstrated that DACH1 was a favorable factor while EYA2 and SIX1 were risk factors for breast cancer patients. Given the results of Cox proportional hazard regression analysis, two members of RDGN were involved in the present predictive model and patients with high model index had poorer outcomes. Conclusion This study showed that aberrant RDGN expression was an unfavorable factor for breast cancer. This RDGN-based comprehensively framework was meaningful for predicting the prognosis of breast cancer patients.
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Affiliation(s)
- Bing Dong
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Suxia Luo
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Anping Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.,Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
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13
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Inhibitory Effects of Tangeretin, A Citrus Peel-Derived Flavonoid, on Breast Cancer Stem Cell Formation through Suppression of Stat3 Signaling. Molecules 2020; 25:molecules25112599. [PMID: 32503228 PMCID: PMC7321155 DOI: 10.3390/molecules25112599] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/01/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified compound was identified as tangeretin by using nuclear magnetic resonance (NMR). Tangeretin inhibited cell proliferation, CSC formation and tumor growth, and modestly induced apoptosis in CSCs. The frequency of a subpopulation with a CSC phenotype (CD44+/CD24-) was reduced by tangeretin. Tangeretin reduced the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3). Our results in this study show that tangeretin inhibits the Stat3 signaling pathway and induces CSC death, indicating that tangeretin may be a potential natural compound that targets breast cancer cells and CSCs.
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14
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Velázquez-Quesada I, Ruiz-Moreno AJ, Casique-Aguirre D, Aguirre-Alvarado C, Cortés-Mendoza F, de la Fuente-Granada M, García-Pérez C, Pérez-Tapia SM, González-Arenas A, Segura-Cabrera A, Velasco-Velázquez MA. Pranlukast Antagonizes CD49f and Reduces Stemness in Triple-Negative Breast Cancer Cells. Drug Des Devel Ther 2020; 14:1799-1811. [PMID: 32494122 PMCID: PMC7229803 DOI: 10.2147/dddt.s247730] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/10/2020] [Indexed: 01/16/2023] Open
Abstract
INTRODUCTION Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. MATERIALS AND METHODS We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. RESULTS Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. CONCLUSION Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.
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Affiliation(s)
- Inés Velázquez-Quesada
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Research and Development in Bioprocess Unit, National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Angel J Ruiz-Moreno
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Graduate Program in Biomedical Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Department of Drug Design, Graduate School of Science and Engineering, University of Groningen (RUG), Groningen, The Netherlands
| | - Diana Casique-Aguirre
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Charmina Aguirre-Alvarado
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Fabiola Cortés-Mendoza
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Graduate Program in Biochemical Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Marisol de la Fuente-Granada
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Carlos García-Pérez
- Center for Genomic Biotechnology, Instituto Politécnico Nacional, Reynosa, Tamaulipas, Mexico
| | - Sonia M Pérez-Tapia
- Research and Development in Bioprocess Unit, National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City, Mexico
- National Laboratory for Specialized Services of Investigation, Development and Innovation (I+D+i) for Pharma Chemicals and Biotechnological Products, LANSEIDI-FarBiotec-CONACyT, Mexico City, Mexico
| | - Aliesha González-Arenas
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Aldo Segura-Cabrera
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
| | - Marco A Velasco-Velázquez
- Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Peripherical Unit for Research in Translational Biomedicine, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Yu S, Yi M, Xu L, Qin S, Li A, Wu K. CXCL1 as an Unfavorable Prognosis Factor Negatively Regulated by DACH1 in Non-small Cell Lung Cancer. Front Oncol 2020; 9:1515. [PMID: 31998654 PMCID: PMC6966305 DOI: 10.3389/fonc.2019.01515] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/16/2019] [Indexed: 12/25/2022] Open
Abstract
Background: Interaction between cancer cells with microenvironment is essential for cancer progression, therapeutic resistance and prognosis. Chemokine CXCL1 shows variable roles in the development of cancers. DACH1 has been considered as a tumor suppressor and represses the expressions of several chemokines. The relationship between CXCL1 and DACH1 in non-small cell lung cancer (SCLC) deserves further investigation. Methods: Immunohistochemistry staining was performed on tumor tissue microarrays from lung cancer patients to detect CXCL1 protein. The CXCL1 concentration in the serum of adenocarcinoma patients was measured by ELISA. The CXCL1 protein secreted by cancer cell lines was detected by SearchLight proteome array and human cytokine antibody array. The meta-analysis of CXCL1 expression form public databases was performed and correlation between CXCL1 and DACH1 was analyzed. Moreover, the association between clinicopathological features and prognosis with CXCL1 and DACH1 was analyzed by tissue array and KM-plotter from public database. Results: The protein abundance of CXCL1 in lung cancer tissues was significantly higher than that in adjacent normal tissues. CXCL1 was closely related to TNM stage, tumor size, and lymph node metastasis and predicted worse overall survival in adenocarcinoma. The level of CXCL1 in the peripheral blood of adenocarcinoma patients also significantly elevated and positively related with clinical stage. The meta-analysis demonstrated that CXCL1 mRNA level was increased in lung cancer tissues and high level of CXCL1 indicated tumor progression in lung adenocarcinoma. In addition, public database analyses showed that CXCL1 negatively correlated with DACH1. Stable overexpressing DACH1 in cultured lung cancer cells remarkably decreased CXCL1 protein. Moreover, ectopic expression of DACH1 significantly inhibited the expression of CXCL1, Ki67, and cyclin D1 in tumor tissues compared with A549 cells with empty vector. Survival analysis showed that high CXCL1 and low DACH1 indicated poor overall survival and progression-free survival. Conclusion: CXCL1 is closely associated with tumor progression and poor survival. DACH1 significantly inhibits the expression of CXCL1 and indicates good prognosis. Therefore, combined detection of CXCL1 and DACH1 could more precisely predict prognosis of lung adenocarcinoma.
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Affiliation(s)
- Shengnan Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Linping Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Shuang Qin
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Anping Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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16
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Vásquez-Bochm LX, Velázquez-Paniagua M, Castro-Vázquez SS, Guerrero-Rodríguez SL, Mondragon-Peralta A, De La Fuente-Granada M, Pérez-Tapia SM, González-Arenas A, Velasco-Velázquez MA. Transcriptome-based identification of lovastatin as a breast cancer stem cell-targeting drug. Pharmacol Rep 2019; 71:535-544. [PMID: 31026757 DOI: 10.1016/j.pharep.2019.02.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 01/27/2019] [Accepted: 02/15/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Breast cancer is a neoplastic disease with high morbidity and mortality in women worldwide. Breast cancer stem cells (CSCs) have a significant function in tumor growth, recurrence, and therapeutic resistance. Thus, CSCs have been pointed as targets of new therapies for breast cancer. Herein, we aimed to repurpose certain drugs as breast CSC-targeting agents. METHODS We compared a consensus breast CSC signature with the transcriptomic changes that were induced by over 1300 bioactive compounds using Connectivity Map. The effects of the selected drugs on SOX2 promoter transactivation, SOX2 expression, viability, clonogenicity, and ALDH activity in breast cancer cells were analyzed by luciferase assay, western blot, MTT assay, mammosphere formation assay, and ALDEFLUOR® test, respectively. Gene Set Enrichment Analysis (GSEA) was performed using the gene expression data from mammary tumors of mice that were treated with lovastatin. RESULTS Five drugs (fasudil, pivmecillinam, ursolic acid, 16,16-dimethylprostaglandin E2, and lovastatin) induced signatures that correlated negatively with the query CSC signature. In vitro, lovastatin inhibited SOX2 promoter transactivation, and reduced the efficiency of mammosphere formation and the percentage of ALDH+ cells. Mevalonate mitigated the effects of lovastatin, suggesting that the targeting of CSCs by lovastatin was mediated by the inhibition of its reported target, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). By GSEA, lovastatin downregulated genes that are involved in stemness and invasiveness in mammary tumors, corroborating our in vitro findings. CONCLUSION Lovastatin is a breast CSC-targeting drug. The inhibition of HMGCR might develop new adjuvant therapeutic strategies for breast tumors.
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Affiliation(s)
- Luz X Vásquez-Bochm
- Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico; Graduate Program in Chemical Sciences, UNAM, Mexico City, Mexico
| | - Mireya Velázquez-Paniagua
- Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico; Department of Physiology, School of Medicine, UNAM, Mexico City, Mexico
| | - Sandra S Castro-Vázquez
- Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico
| | - Sandra L Guerrero-Rodríguez
- Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico
| | - Abimael Mondragon-Peralta
- Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico
| | - Marisol De La Fuente-Granada
- Department of Genomic Medicine and Environmental Toxicology, Institute of Biomedical Research (IIB), UNAM, Mexico City, Mexico
| | - Sonia M Pérez-Tapia
- Unit for Development and Research in Bioprocesses (UDIBI), National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico
| | - Aliesha González-Arenas
- Department of Genomic Medicine and Environmental Toxicology, Institute of Biomedical Research (IIB), UNAM, Mexico City, Mexico
| | - Marco A Velasco-Velázquez
- Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico; Unit for Research in Translational Biomedicine, Research Division, School of Medicine, UNAM, Mexico City, Mexico.
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Kingsbury TJ, Kim M, Civin CI. Regulation of cancer stem cell properties by SIX1, a member of the PAX-SIX-EYA-DACH network. Adv Cancer Res 2019; 141:1-42. [PMID: 30691681 DOI: 10.1016/bs.acr.2018.12.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The PAX-SIX-EYA-DACH network (PSEDN) is a central developmental transcriptional regulatory network from Drosophila to humans. The PSEDN is comprised of four conserved protein families; including paired box (PAX), sine oculis (SIX), eyes absent (EYA), and dachshund (DACH). Aberrant expression of PSEDN members, particularly SIX1, has been observed in multiple human cancers, where SIX1 expression correlates with increased aggressiveness and poor prognosis. In conjunction with its transcriptional activator EYA, the SIX1 transcription factor increases cancer stem cell (CSC) numbers and induces epithelial-mesenchymal transition (EMT). SIX1 promotes multiple hallmarks and enabling characteristics of cancer via regulation of cell proliferation, senescence, apoptosis, genome stability, and energy metabolism. SIX1 also influences the tumor microenvironment, enhancing recruitment of tumor-associated macrophages and stimulating angiogenesis, to promote tumor development and progression. EYA proteins are multifunctional, possessing a transcriptional activation domain and tyrosine phosphatase activity, that each contributes to cancer stem cell properties. DACH proteins function as tumor suppressors in solid cancers, opposing the actions of SIX-EYA and reducing CSC prevalence. Multiple mechanisms can lead to increased SIX1 expression, including loss of SIX1-targeting tumor suppressor microRNAs (miRs), whose expression correlates inversely with SIX1 expression in cancer patient samples. In this review, we discuss the major mechanisms by which SIX1 confers CSC and EMT features and other important cancer cell characteristics. The roles of EYA and DACH in CSCs and cancer progression are briefly highlighted. Finally, we summarize the clinical significance of SIX1 in cancer to emphasize the potential therapeutic benefits of effective strategies to disrupt PSEDN protein interactions and functions.
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18
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Jiao X, Li Z, Wang M, Katiyar S, Di Sante G, Farshchian M, South AP, Cocola C, Colombo D, Reinbold R, Zucchi I, Wu K, Tabas I, Spike BT, Pestell RG. Dachshund Depletion Disrupts Mammary Gland Development and Diverts the Composition of the Mammary Gland Progenitor Pool. Stem Cell Reports 2018; 12:135-151. [PMID: 30554919 PMCID: PMC6335505 DOI: 10.1016/j.stemcr.2018.11.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 12/31/2022] Open
Abstract
DACH1 abundance is reduced in human malignancies, including breast cancer. Herein DACH1 was detected among multipotent fetal mammary stem cells in the embryo, among mixed lineage precursors, and in adult basal cells and (ERα+) luminal progenitors. Dach1 gene deletion at 6 weeks in transgenic mice reduced ductal branching, reduced the proportion of mammary basal cells (Lin− CD24med CD29high) and reduced abundance of basal cytokeratin 5, whereas DACH1 overexpression induced ductal branching, increased Gata3 and Notch1, and expanded mammosphere formation in LA-7 breast cells. Mammary gland-transforming growth factor β (TGF-β) activity, known to reduce ductal branching and to reduce the basal cell population, increased upon Dach1 deletion, associated with increased SMAD phosphorylation. Association of the scaffold protein Smad anchor for receptor activation with Smad2/3, which facilitates TGF-β activation, was reduced by endogenous DACH1. DACH1 increases basal cells, enhances ductal formation and restrains TGF-β activity in vivo.
Dach1 is expressed in mammary gland fetal stem cells and adult luminal cells Dach1 expands mammary gland basal/myoepithelial cells Dach1 induces post-natal mammary gland ductal formation Dach1 retrains TGF-β activity in the mammary gland in vivo
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Affiliation(s)
- Xuanmao Jiao
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA
| | - Zhiping Li
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA
| | - Min Wang
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA
| | - Sanjay Katiyar
- Department of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10(th) Street, Philadelphia, PA 19107, USA
| | - Gabriele Di Sante
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA
| | - Mehdi Farshchian
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10(th) Street, Philadelphia, PA 19107, USA
| | - Andrew P South
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10(th) Street, Philadelphia, PA 19107, USA
| | - Cinzia Cocola
- Istituto Tecnologie Biomediche, Consiglio Nazionale Delle Ricerche, Via Cervi 93, Segrate, 20090 Milano, Italy
| | - Daniele Colombo
- Istituto Tecnologie Biomediche, Consiglio Nazionale Delle Ricerche, Via Cervi 93, Segrate, 20090 Milano, Italy
| | - Rolland Reinbold
- Istituto Tecnologie Biomediche, Consiglio Nazionale Delle Ricerche, Via Cervi 93, Segrate, 20090 Milano, Italy
| | - Ileana Zucchi
- Istituto Tecnologie Biomediche, Consiglio Nazionale Delle Ricerche, Via Cervi 93, Segrate, 20090 Milano, Italy
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
| | - Ira Tabas
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Benjamin T Spike
- Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Room 2505, Salt Lake City, UT 84112, USA
| | - Richard G Pestell
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637551, Singapore.
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19
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Gaspar P, Almudi I, Nunes MDS, McGregor AP. Human eye conditions: insights from the fly eye. Hum Genet 2018; 138:973-991. [PMID: 30386938 DOI: 10.1007/s00439-018-1948-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 10/20/2018] [Indexed: 12/22/2022]
Abstract
The fruit fly Drosophila melanogaster has served as an excellent model to study and understand the genetics of many human diseases from cancer to neurodegeneration. Studying the regulation of growth, determination and differentiation of the compound eyes of this fly, in particular, have provided key insights into a wide range of diseases. Here we review the regulation of the development of fly eyes in light of shared aspects with human eye development. We also show how understanding conserved regulatory pathways in eye development together with the application of tools for genetic screening and functional analyses makes Drosophila a powerful model to diagnose and characterize the genetics underlying many human eye conditions, such as aniridia and retinitis pigmentosa. This further emphasizes the importance and vast potential of basic research to underpin applied research including identifying and treating the genetic basis of human diseases.
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Affiliation(s)
- Pedro Gaspar
- Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK
| | - Isabel Almudi
- Centro Andaluz de Biología del Desarrollo, CSIC/ Universidad Pablo de Olavide, Carretera de Utrera Km1, 41013, Sevilla, Spain
| | - Maria D S Nunes
- Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK
| | - Alistair P McGregor
- Department of Biological and Medical Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.
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20
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Zhang J, Ren X, Wang B, Cao J, Tian L, Liu M. Effect of DACH1 on proliferation and invasion of laryngeal squamous cell carcinoma. Head Face Med 2018; 14:20. [PMID: 30261897 PMCID: PMC6161397 DOI: 10.1186/s13005-018-0177-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 09/19/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To investigate the effect of DACH1 over-expression on proliferation and invasion of laryngeal squamous cell carcinoma (LSCC). METHODS The 120 cases of LSCC tumors and 114 adjacent non-neoplastic tissues were collected to detect the expression of DACH1 by immunohistochemistry. The changes of DACH1 expression from each group were assessed and correlated to the clinical parameters of the patients. Plasmid-DACH1 was transfected into Hep-2 cells to up-regulate the expression of DACH1C. Real-time PCR, Western blot, CCK8 and transwell assay were used to verify the cell proliferation and invasion after plasmid-DACH1 transfection. RESULTS The results indicated that DACH1 was downregulated in LSCC tissues as compared to corresponding adjacent non-neoplastic tissues. Decreased expression of DACH1 was found in the tumors upraglottic tumor, lymph node metastases, T3-4 stage and advanced clinical stage. In Hep-2 cells, transfection with plasmid-DACH1 could suppress cell proliferation, invasion and induce G1 phase extension in cell cycle. CONCLUSIONS DACH1 may act as a tumor suppressor gene and could be a potential target for therapeutic intervention of LSCC.
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Affiliation(s)
- Jiarui Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Xiuxia Ren
- Department of Otorhinolaryngology, Head and Neck Surgery, Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Bo Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Jing Cao
- Department of Otorhinolaryngology, Head and Neck Surgery, Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Linli Tian
- Department of Otorhinolaryngology, Head and Neck Surgery, Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China.
| | - Ming Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China.
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21
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Wang J, Zou Y, Wu X, Chen M, Zhang S, Lu X, Wang Q. DACH1 inhibits glioma invasion and tumor growth via the Wnt/catenin pathway. Onco Targets Ther 2018; 11:5853-5863. [PMID: 30271168 PMCID: PMC6149903 DOI: 10.2147/ott.s168314] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background/aim Glioma is the most common and malignant nervous system tumor and is associated with high-grade malignancy and high recurrence. The mammalian Dachshund1 (DACH1) is a recognized anti-tumor site and has low expression in several malignant tumors, including glioma. We designed and conducted this study to further determine the mechanism of DACH1 in glioma. Patients and methods The data collected from specimens of patients with glioma from GSE16011 and REMBRANDT databases were analyzed. The effect of DACH1 on proliferation, migration, and invasion of U87 and U251 cell lines was analyzed in vitro. The symbol targets of the Wnt/β-catenin pathway were also evaluated through Western blot. Results DACH1 deficiency was found in glioma tissues, and the DACH1 level was negatively correlated with the tumor malignancy. DACH1 overexpression inhibited the tumor proliferation, migration, and invasion. High expression of DACH1 also dampened the Wnt/β-catenin pathway, and the activation of the Wnt/β-catenin pathway partly led to the limited proliferation in glioma cells. Conclusion Downregulation of DACH1 was related to the malignancy and poor prognosis of patients with glioma, and DACH1 overexpression inhibited the tumor proliferation via the Wnt/β-catenin pathway. These findings might assist in the discovery of novel potential diagnostic and therapeutic targets for DACH1, thereby reducing the malignancy and recurrence of glioma.
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Affiliation(s)
- Jing Wang
- Neurosurgery, The Affiliated Wuxi No 2 People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China,
| | - Yan Zou
- Neurosurgery, The Affiliated Wuxi No 2 People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China,
| | - Xuechao Wu
- Neurosurgery, The Affiliated Wuxi No 2 People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China,
| | - Mu Chen
- Neurosurgery, The Affiliated Wuxi No 2 People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China,
| | - Shuai Zhang
- Neurosurgery, The Affiliated Wuxi No 2 People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China,
| | - Xiaojie Lu
- Neurosurgery, The Affiliated Wuxi No 2 People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China,
| | - Qing Wang
- Neurosurgery, The Affiliated Wuxi No 2 People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China,
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22
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Menzel-Severing J, Zenkel M, Polisetti N, Sock E, Wegner M, Kruse FE, Schlötzer-Schrehardt U. Transcription factor profiling identifies Sox9 as regulator of proliferation and differentiation in corneal epithelial stem/progenitor cells. Sci Rep 2018; 8:10268. [PMID: 29980721 PMCID: PMC6035181 DOI: 10.1038/s41598-018-28596-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 06/26/2018] [Indexed: 02/08/2023] Open
Abstract
Understanding transcription factor (TF) regulation of limbal epithelial stem/progenitor cells (LEPCs) may aid in using non-ocular cells to regenerate the corneal surface. This study aimed to identify and characterize TF genes expressed specifically in LEPCs isolated from human donor eyes by laser capture microdissection. Using a profiling approach, preferential limbal expression was found for SoxE and SoxF genes, particularly for Sox9, which showed predominantly cytoplasmic localization in basal LEPCs and nuclear localization in suprabasal and corneal epithelial cells, indicating nucleocytoplasmic translocation and activation during LEPC proliferation and differentiation. Increased nuclear localization of Sox9 was also observed in activated LEPCs following clonal expansion and corneal epithelial wound healing. Knockdown of SOX9 expression in cultured LEPCs by RNAi led to reduced expression of progenitor cell markers, e.g. keratin 15, and increased expression of differentiation markers, e.g. keratin 3. Furthermore, SOX9 silencing significantly suppressed the proliferative capacity of LEPCs and reduced levels of glycogen synthase kinase 3 beta (GSK-3ß), a negative regulator of Wnt/ß-catenin signaling. Sox9 expression, in turn, was significantly suppressed by treatment of LEPCs with exogenous GSK-3ß inhibitors and enhanced by small molecule inhibitors of Wnt signaling. Our results suggest that Sox9 and Wnt/ß-catenin signaling cooperate in mutually repressive interactions to achieve a balance between quiescence, proliferation and differentiation of LEPCs in the limbal niche. Future molecular dissection of Sox9-Wnt interaction and mechanisms of nucleocytoplasmic shuttling of Sox9 may aid in improving the regenerative potential of LEPCs and the reprogramming of non-ocular cells for corneal surface regeneration.
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Affiliation(s)
- Johannes Menzel-Severing
- Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Matthias Zenkel
- Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Naresh Polisetti
- Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Elisabeth Sock
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Wegner
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Friedrich E Kruse
- Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Liu Q, Li A, Yu S, Qin S, Han N, Pestell RG, Han X, Wu K. DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis. J Hematol Oncol 2018; 11:53. [PMID: 29636079 PMCID: PMC5894143 DOI: 10.1186/s13045-018-0597-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 03/26/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND C-X-C motif ligand 8 (CXCL8), known as a proinflammatory chemokine, exerts multiple effects on the proliferation, invasion, and migration of tumor cells via the autocrine or paracrine manner. Conversely, the human Dachshund homologue 1 (DACH1) is recognized as a tumor suppressor which retards the progression of various cancers. In prostate cancer, it has been demonstrated that DACH1 was negatively correlated with the expression of CXCL8 and able to antagonize the effects of CXCL8 on cellular migration. Herein, we explored the mechanisms by which DACH1 regulated the CXCL8 in non-small cell lung cancer (NSCLC). METHODS Public microarray and Kaplan-Meier plotter datasets were analyzed. Blood serum samples from lung adenocarcinoma (ADC) patients were collected for enzyme-linked immunosorbent assay (ELISA) analysis. Immunohistochemical staining was conducted on tissue microarray. Cell lines with stable expression of DACH1 were established, and relative gene expression was measured by Western blot, ELISA, real-time PCR, and human cytokine array. Correspondingly, cell lines transfected with shDACH1 were established, and relative gene expression was measured by real-time PCR and immunofluorescence array. Functional studies were performed by transwell and xenograft mice models. Luciferase reporter gene assay was applied to measure the regulation of DACH1 on CXCL8. RESULTS Our study indicated that CXCL8 both at the mRNA and protein level was associated with the high tumor burden of ADC. Correlational analyses in ADC cell lines and ADC tissues showed that DACH1 was inversely correlated with CXCL8. Meanwhile, patients with high DACH1 expression and low CXCL8 expression had prolonged time to death and recurrence. Moreover, we verified the inhibitory effects of DACH1 on CXCL8 both in vitro and in vivo. Mechanism studies proved that DACH1 transcriptionally repressed CXCL8 promoter activity through activator protein-1 (AP-1) and nuclear transcription factor-kappa B (NF-κB) sites. CONCLUSIONS Our study proved that CXCL8 acted as an unfavorable factor promoting to tumor progression and poor prognosis of ADC, while DACH1 antagonized CXCL8 to provide a favorable survival of ADC patients. Double detection of DACH1 and CXCL8 may provide a precise information for further evaluating the prognosis of ADC patients.
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Affiliation(s)
- Qian Liu
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Anping Li
- grid.412633.1Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China
| | - Shengnan Yu
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Shuang Qin
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Na Han
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Richard G. Pestell
- Pennsylvania Cancer and Regenerative Medicine Research Center, Wynnewood, PA 19096 USA
| | - Xinwei Han
- grid.412633.1Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China
| | - Kongming Wu
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
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Xiong H, Zhao W, Wang J, Seifer BJ, Ye C, Chen Y, Jia Y, Chen C, Shen J, Wang L, Sui X, Zhou J. Oncogenic mechanisms of Lin28 in breast cancer: new functions and therapeutic opportunities. Oncotarget 2018; 8:25721-25735. [PMID: 28147339 PMCID: PMC5421965 DOI: 10.18632/oncotarget.14891] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 01/11/2017] [Indexed: 12/25/2022] Open
Abstract
The RNA binding protein Lin28 is best known for the critical role in cell development, recent researches also have implied its oncogenic function in various human cancers, including breast cancer. Specifically, aberrant Lin28 participates in multiple pathological processes, such as proliferation, metastasis, radiotherapy and chemotherapy resistance, metabolism, immunity and inflammation as well as stemness. In this review, we summarize the let-7-dependent and let-7-independent mechanism regulated by Lin28, focusing on its relation with tumor hallmarks in breast cancer, and subsequently discuss our present knowledge of Lin28 to develop a molecular-based therapeutic strategy against breast cancer.
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Affiliation(s)
- Hanchu Xiong
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Wenhe Zhao
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Ji Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | | | - Chenyang Ye
- Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education), Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yongxia Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yunlu Jia
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Cong Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jianguo Shen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Linbo Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xinbing Sui
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China.,Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jichun Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China
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25
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The retinal determination gene network: from developmental regulator to cancer therapeutic target. Oncotarget 2018; 7:50755-50765. [PMID: 27203207 PMCID: PMC5226618 DOI: 10.18632/oncotarget.9394] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 04/28/2016] [Indexed: 11/25/2022] Open
Abstract
Although originally identified for its function in Drosophila melanogaster eye specification, the Retinal Determination Gene Network (RDGN) is essential for the development of multiple organs in mammals. The RDGN regulates proliferation, differentiation and autocrine signaling, and interacts with other key signaling pathways. Aberrant expression of RDGN members such as DACH, EYA and SIX contributes to tumor initiation and progression; indeed, the levels of RDGN members are clinically prognostic factors in various cancer types. Stimulation or suppression of the activities of these crucial components can block cancer cell proliferation, prevent cancer stem cell expansion and even reverse the EMT process, thereby attenuating malignant phenotypes. Thus, cancer therapeutic interventions targeting RDGN members should be pursued in future studies.
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26
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Rangel R, Guzman-Rojas L, Kodama T, Kodama M, Newberg JY, Copeland NG, Jenkins NA. Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer. Cancer Res 2017; 77:4089-4101. [DOI: 10.1158/0008-5472.can-17-0785] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 04/28/2017] [Accepted: 06/05/2017] [Indexed: 11/16/2022]
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DACH1 suppresses breast cancer as a negative regulator of CD44. Sci Rep 2017; 7:4361. [PMID: 28659634 PMCID: PMC5489534 DOI: 10.1038/s41598-017-04709-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/18/2017] [Indexed: 02/06/2023] Open
Abstract
Dachshund homolog 1 (DACH1), a key cell fate determination factor, contributes to tumorigenesis, invasion, metastasis of human breast neoplasm. However, the exact molecular mechanisms for the anti-tumor roles of DACH1 in breast carcinoma are still lack of extensive understanding. Herein, we utilized immunohistochemistry (IHC) staining and public microarray data analysis showing that DACH1 was higher in normal breast, low-grade and luminal-type cancer in comparison with breast carcinoma, high-grade and basal-like tumors respectively. Additionally, both correlation analysis of public databases of human breast carcinoma and IHC analysis of mice xenograft tumors demonstrated that DACH1 inversely related to cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) inducers and basal-enriched molecules, while cluster of differentiation 44 (CD44) behaved in an opposite manner. Furthermore, mice transplanted tumor model indicated that breast cancer cells Met-1 with up-regulation of DACH1 were endowed with remarkably reduced potential of tumorigenesis. Importantly, meta-analysis of 19 Gene Expression Omnibus (GEO) databases of breast cancer implicated that patients with higher DACH1 expression had prolonged time to death, recurrence and metastasis, while CD44 was a promising biomarker predicting worse overall survival (OS) and metastasis-free survival (MFS). Collectively, our study indicated that CD44 might be a novel target of DACH1 in breast carcinoma.
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28
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Yu Z, Sun Y, She X, Wang Z, Chen S, Deng Z, Zhang Y, Liu Q, Liu Q, Zhao C, Li P, Liu C, Feng J, Fu H, Li G, Wu M. SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B. J Hematol Oncol 2017; 10:115. [PMID: 28595628 PMCID: PMC5465582 DOI: 10.1186/s13045-017-0483-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 05/31/2017] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. METHODS Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. RESULTS SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. CONCLUSION SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.
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Affiliation(s)
- Zhibin Yu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China
| | - Yingnan Sun
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
| | - Xiaoling She
- The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Zeyou Wang
- The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Shuai Chen
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
| | - Zhiyong Deng
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
| | - Yan Zhang
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China
| | - Qiang Liu
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Qing Liu
- The Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Chunhua Zhao
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
| | - Peiyao Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China
| | - Changhong Liu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China
| | - Jianbo Feng
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China
| | - Haijuan Fu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China
| | - Guiyuan Li
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China
| | - Minghua Wu
- Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, Hunan, China.
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, 410008, China.
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Sun JG, Chen XW, Zhang LP, Wang J, Diehn M. Yap1 promotes the survival and self-renewal of breast tumor initiating cells via inhibiting Smad3 signaling. Oncotarget 2016; 7:9692-706. [PMID: 26695440 PMCID: PMC4891077 DOI: 10.18632/oncotarget.6655] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Accepted: 10/08/2015] [Indexed: 12/27/2022] Open
Abstract
Tumor initiating cells (TICs) serve as the root of tumor growth. After identifying TICs in spontaneous breast tumors of the MMTV-Wnt1 mouse model, we confirmed the specific expression and activation of Yes-associated protein 1 (Yap1) within TICs. To investigate the role of Yap1 in the self-renewal of breast TICs and the underlying mechanism, we sorted CD49fhighEpCAMlow cells as breast TICs. Active Yap1 with ectopic expression in breast TICs promoted their colony formation in vitro (p< 0.01) and self-renewal in vivo (p< 0.01), and led to a 4-fold increase in TIC frequency (p< 0.05). A conditional knock-out mouse was reconstructed to generate Yap1 knock-out breast tumors. The loss of Yap1 led to a dramatic growth disadvantage of breast TICs in vitro (p< 0.01) and in vivo (p< 0.01), and it also led to an over 200-fold decrease in TIC frequency (p< 0.01). The expression of active Yap1 was negatively correlated with that of phosphorylated Smad3 (p-Smad3). Transforming growth factor β (TGF-β) served as a strong enhancer of Smad3 and an inhibitor of clonogenesis of TICs. The presence of SIS3, a specific inhibitor of Smad3, could rescue the TGF-β -induced growth inhibition and reverse the Smad3 inhibition by Yap1. Analysis of a database containing 2,072 human breast cancer samples showed that higher expressions of Yap1 correlated with a poorer outcome of a 15-year survival rate and median overall survival (mOS)in patients, especially in those with basal breast tumors without estrogen receptor 1 (ER) expression. The findings indicate that active Yap1 promotes the self-renewal of breast TICs by inhibiting Smad3 signaling.
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Affiliation(s)
- Jian-Guo Sun
- Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.,Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China
| | - Xie-Wan Chen
- Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China
| | - Lu-Ping Zhang
- Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China
| | - Jiang Wang
- Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China
| | - Max Diehn
- Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
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30
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Uehiro N, Sato F, Pu F, Tanaka S, Kawashima M, Kawaguchi K, Sugimoto M, Saji S, Toi M. Circulating cell-free DNA-based epigenetic assay can detect early breast cancer. Breast Cancer Res 2016; 18:129. [PMID: 27993161 PMCID: PMC5168705 DOI: 10.1186/s13058-016-0788-z] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 12/01/2016] [Indexed: 12/29/2022] Open
Abstract
Background Circulating cell-free DNA (cfDNA) has recently been recognized as a resource for biomarkers of cancer progression, treatment response, and drug resistance. However, few have demonstrated the usefulness of cfDNA for early detection of cancer. Although aberrant DNA methylation in cfDNA has been reported for more than a decade, its diagnostic accuracy remains unsatisfactory for cancer screening. Thus, the aim of the present study was to develop a highly sensitive cfDNA-based system for detection of primary breast cancer (BC) using epigenetic biomarkers and digital PCR technology. Methods Array-based genome-wide DNA methylation analysis was performed using 56 microdissected breast tissue specimens, 34 cell lines, and 29 blood samples from healthy volunteers (HVs). Epigenetic markers for BC detection were selected, and a droplet digital methylation-specific PCR (ddMSP) panel with the selected markers was established. The detection model was constructed by support vector machine and evaluated using cfDNA samples. Results The methylation array analysis identified 12 novel epigenetic markers (JAK3, RASGRF1, CPXM1, SHF, DNM3, CAV2, HOXA10, B3GNT5, ST3GAL6, DACH1, P2RX3, and chr8:23572595) for detecting BC. We also selected four internal control markers (CREM, GLYATL3, ELMOD3, and KLF9) that were identified as infrequently altered genes using a public database. A ddMSP panel using these 16 markers was developed and detection models were constructed with a training dataset containing cfDNA samples from 80 HVs and 87 cancer patients. The best detection model adopted four methylation markers (RASGRF1, CPXM1, HOXA10, and DACH1) and two parameters (cfDNA concentration and the mean of 12 methylation markers), and, and was validated in an independent dataset of 53 HVs and 58 BC patients. The area under the receiver operating characteristic curve for cancer-normal discrimination was 0.916 and 0.876 in the training and validation dataset, respectively. The sensitivity and the specificity of the model was 0.862 (stages 0-I 0.846, IIA 0.862, IIB-III 0.818, metastatic BC 0.935) and 0.827, respectively. Conclusion Our epigenetic-marker-based system distinguished BC patients from HVs with high accuracy. As detection of early BC using this system was comparable with that of mammography screening, this system would be beneficial as an optional method of screening for BC. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0788-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Natsue Uehiro
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Fumiaki Sato
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| | - Fengling Pu
- Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Sunao Tanaka
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiro Kawashima
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kosuke Kawaguchi
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Shigehira Saji
- Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan
| | - Masakazu Toi
- Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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31
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Davis TL, Rebay I. Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks. Dev Biol 2016; 421:93-107. [PMID: 27979656 DOI: 10.1016/j.ydbio.2016.12.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/03/2016] [Accepted: 12/03/2016] [Indexed: 02/07/2023]
Abstract
Among the mechanisms that steer cells to their correct fate during development, master regulatory networks are unique in their sufficiency to trigger a developmental program outside of its normal context. In this review we discuss the key features that underlie master regulatory potency during normal and ectopic development, focusing on two examples, the retinal determination gene network (RDGN) that directs eye development in the fruit fly and the pluripotency gene network (PGN) that maintains cell fate competency in the early mammalian embryo. In addition to the hierarchical transcriptional activation, extensive positive transcriptional feedback, and cooperative protein-protein interactions that enable master regulators to override competing cellular programs, recent evidence suggests that network topology must also be dynamic, with extensive rewiring of the interactions and feedback loops required to navigate the correct sequence of developmental transitions to reach a final fate. By synthesizing the in vivo evidence provided by the RDGN with the extensive mechanistic insight gleaned from the PGN, we highlight the unique regulatory capabilities that continual reorganization into new hierarchies confers on master control networks. We suggest that deeper understanding of such dynamics should be a priority, as accurate spatiotemporal remodeling of network topology will undoubtedly be essential for successful stem cell based therapeutic efforts.
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Affiliation(s)
- Trevor L Davis
- Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, IL 60637, USA
| | - Ilaria Rebay
- Committee on Development, Regeneration, and Stem Cell Biology, University of Chicago, Chicago, IL 60637, USA; Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
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32
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Sun X, Jiang S, Liu J, Wang H, Zhang Y, Tang SC, Wang J, Du N, Xu C, Wang C, Qin S, Zhang J, Liu D, Zhang Y, Li X, Wang J, Dong J, Wang X, Xu S, Tao Z, Xu F, Zhou J, Wang T, Ren H. MiR-208a stimulates the cocktail of SOX2 and β-catenin to inhibit the let-7 induction of self-renewal repression of breast cancer stem cells and formed miR208a/let-7 feedback loop via LIN28 and DICER1. Oncotarget 2016; 6:32944-54. [PMID: 26460550 PMCID: PMC4741741 DOI: 10.18632/oncotarget.5079] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 07/28/2015] [Indexed: 12/23/2022] Open
Abstract
MiR-208a stimulates cardiomyocyte hypertrophy, fibrosis and β-MHC (β-myosin heavy chain) expression, being involved in cardiovascular diseases. Although miR-208a is known to play a role in cardiovascular diseases, its role in cancer and cancer stem cells (CSCs) remains uncertain. We identified an inverse relationship between miR-208a and let-7a in breast cancer specimens, and found that SOX2, β-catenin and LIN28 are highly expressed in patients with advanced breast cancer opposed to lesser grades. Further, we isolated ALDH1+ CSCs from ZR75–1 and MDA-MB-231 (MM-231) breast cancer cell lines to test the role of miR-208a in breast CSCs (BrCSCs). Our studies showed that overexpression of miR-208a in these cells strongly promoted the proportion of ALDH1+ BrCSCs and continuously stimulated the self-renewal ability of BrCSCs. By using siRNAs of SOX2 and/or β-catenin, we found that miR-208a increased LIN28 through stimulation of both SOX2 and β-catenin. The knockdown of either SOX2 or β-catenin only partially attenuated the functions of miR-208a. Let-7a expression was strongly inhibited in miR-208a overexpressed cancer cells, which was achieved by miR-208a induction of LIN28, and the restoration of let-7a significantly inhibited the miR-208a induction of the number of ALDH1+ cells, inhibiting the propagations of BrCSCs. In let-7a overexpressed ZR75–1 and MM-231 cells, DICER1 activity was significantly inhibited with decreased miR-208a. Let-7a failed to decrease miR-208a expression in ZR75–1 and MM-231 cells with DICER1 knockdown. Our research revealed the mechanisms through which miR-208a functioned in breast cancer and BrCSCs, and identified the miR-208a-SOX2/β-catenin-LIN28-let-7a-DICER1 regulatory feedback loop in regulations of stem cells renewal.
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Affiliation(s)
- Xin Sun
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Shiwen Jiang
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325027, China
| | - Jian Liu
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Huangzhen Wang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Yiwen Zhang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Shou-Ching Tang
- Breast Cancer Program and Interdisciplinary Translational Research Team, Georgia Regents University Cancer Center, Augusta, Georgia, 30912, United States.,Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Jichang Wang
- Neurosurgery Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Ning Du
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Chongwen Xu
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Chenguang Wang
- Institute of Radiation Medicine, the Chinese Academy of Medical Sciences, Nankai District, Tianjing 300192, China
| | - Sida Qin
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Jia Zhang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Dapeng Liu
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Yunfeng Zhang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Xiaojun Li
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Jiansheng Wang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Jun Dong
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Xin Wang
- Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
| | - Shaohua Xu
- Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China
| | - Zhen Tao
- Department of Radiation Oncology, Tianjin Cancer Institute and Hospital Affiliated to Tianjin Medical University, Tianjin, 300060, China
| | - Fei Xu
- Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Jie Zhou
- Department of Breast Oncology, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, 510182, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Hong Ren
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China
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33
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Ju X, Jiao X, Ertel A, Casimiro MC, Di Sante G, Deng S, Li Z, Di Rocco A, Zhan T, Hawkins A, Stoyanova T, Andò S, Fatatis A, Lisanti MP, Gomella LG, Languino LR, Pestell RG. v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1. Cancer Res 2016; 76:6723-6734. [PMID: 27634768 DOI: 10.1158/0008-5472.can-15-3327] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 07/18/2016] [Accepted: 08/18/2016] [Indexed: 01/06/2023]
Abstract
Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, epitope characteristics, and prostatosphere formation. Cyclin D1 was induced by v-Src, and Src kinase induction of Trop2 ICD nuclear accumulation required cyclin D1. Cyclin D1 induced abundance of the Trop2 proteolytic cleavage activation components (PS2, TACE) and restrained expression of the inhibitory component of the Trop2 proteolytic complex (Numb). Patients with prostate cancer with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (HR = 4.35). Cyclin D1, therefore, serves as a transducer of v-Src-mediated induction of Trop2 ICD by enhancing abundance of the Trop2 proteolytic activation complex. Cancer Res; 76(22); 6723-34. ©2016 AACR.
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Affiliation(s)
- Xiaoming Ju
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Xuanmao Jiao
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Adam Ertel
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Mathew C Casimiro
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Gabriele Di Sante
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Shengqiong Deng
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Zhiping Li
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Agnese Di Rocco
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Tingting Zhan
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Adam Hawkins
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Tanya Stoyanova
- Department of Microbiology, Immunology, and Molecular Genetics University of California, Los Angeles, California
| | - Sebastiano Andò
- Faculty of Pharmacy, Nutrition, and Health Science, University of Calabria, Arcavacata, Rende CS, Italy
| | - Alessandro Fatatis
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Pharmacology and Physiology and Laboratory Medicine, Drexel University, Philadelphia, Pennsylvania
| | - Michael P Lisanti
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Leonard G Gomella
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Lucia R Languino
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Richard G Pestell
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. .,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
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34
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Zhang L, Wang D, Li Y, Liu Y, Xie X, Wu Y, Zhou Y, Ren J, Zhang J, Zhu H, Su Z. CCL21/CCR7 Axis Contributed to CD133+ Pancreatic Cancer Stem-Like Cell Metastasis via EMT and Erk/NF-κB Pathway. PLoS One 2016; 11:e0158529. [PMID: 27505247 PMCID: PMC4978474 DOI: 10.1371/journal.pone.0158529] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 06/17/2016] [Indexed: 11/26/2022] Open
Abstract
Background Tumor metastasis is driven by malignant cells and stromal cell components of the tumor microenvironment. Cancer stem cells (CSCs) are thought to be responsible for metastasis by altering the tumor microenvironment. Epithelial-mesenchymal transition (EMT) processes contribute to specific stages of the metastatic cascade, promoted by cytokines and chemokines secreted by stromal cell components in the tumor microenvironment. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine ligand 21(CCL21), to mediate metastasis in some cancer cells lines. This study investigated the role of CCL21/CCR7 in promoting EMT and metastasis of cluster of differentiation 133+ (CD133+) pancreatic cancer stem-like cells. Methods Panc-1, AsPC-1, and MIA PaCa-2 pancreatic cancer cells were selected because of their aggressive invasive potentials. CCR7 expression levels were examined in total, CD133+ and CD133− cell fractions by Immunofluorescence analysis and real time-quantitative polymerase chain reaction (RT-qPCR). The role of CCL21/CCR7 in mediating metastasis and survival of CD133+ pancreatic cancer stem-like cells was detected by Transwell assays and flow cytometry, respectively. EMT and lymph node metastasis related markers (E-cadherin, N- cadherin, LYVE-1) were analyzed by western blot. CCR7 expression levels were analyzed by immunohistochemical staining and RT-qPCR in resected tumor tissues, metastatic lymph nodes, normal lymph nodes and adjacent normal tissues from patients with pancreatic carcinoma. Results CCR7 expression was significantly increased in CD133+ pancreatic cancer stem-like cells, resected pancreatic cancer tissues, and metastatic lymph nodes, compared with CD133− cancer cells, adjacent normal tissues and normal lymph nodes, respectively. CCL21/CCR7 promoted metastasis and survival of CD133+ pancreatic cancer stem-like cells and regulated CD133+ pancreatic cancer stem-like cells metastasis by modulating EMT and Erk/NF-κB pathway. Conclusions These results indicate a specific role for CCL21/CCR7 in promoting EMT and metastasis in CD133+ pancreatic cancer stem-like cells. Furthermore the data also indicated the potential importance of developing therapeutic strategies targeting cancer stem-like cells and CCL21/CCR7 for reducing metastasis.
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Affiliation(s)
- Lirong Zhang
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Dongqing Wang
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- * E-mail: (DW); (HZ); (ZS)
| | - Yumei Li
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Yanfang Liu
- Department of Central laboratory, The First People’s Hospital of Zhenjiang, Zhenjiang, 212001, China
| | - Xiaodong Xie
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Yingying Wu
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Yuepeng Zhou
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Jing Ren
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Jianxin Zhang
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
| | - Haitao Zhu
- Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China
- * E-mail: (DW); (HZ); (ZS)
| | - Zhaoliang Su
- Department of Immunology, Jiangsu University, Zhenjiang, 212013, China
- * E-mail: (DW); (HZ); (ZS)
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35
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Zhu J, Wu C, Li H, Yuan Y, Wang X, Zhao T, Xu J. DACH1 inhibits the proliferation and invasion of lung adenocarcinoma through the downregulation of peroxiredoxin 3. Tumour Biol 2016; 37:9781-8. [PMID: 26810067 PMCID: PMC4990600 DOI: 10.1007/s13277-016-4811-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 01/06/2016] [Indexed: 12/14/2022] Open
Abstract
In this study, we found the expression of Dachshund 1 (DACH1) is downregulated while peroxiredoxin 3 (PRX3) upregulated in both lung adenocarcinoma tissues and cells. Transfection of DACH1 can significantly downregulate PRX3 expression in targeting lung adenocarcinoma cells. Further experimental results demonstrated the evidence that overexpression of DACH1 resulted in significant retardation of in vitro proliferation and invasion of lung adenocarcinoma cells. Direct upregulation of PRX3 by co-transfection of PRX3 messenger RNA (mRNA) can prevent the above alteration caused by DACH1 transfection. Besides, lower DACH1 expression significantly correlated with tumor diameter and tumor invasion in all the 36 patients diagnosed with lung adenocarcinoma in our hospital during the past months. In conclusion, DACH1 can inhibit the proliferation and invasion of lung adenocarcinoma through the downregulation of PRX3. Decreased expression of DACH1 is involved in the initiation and development of lung cancer, which might be an adverse prognostic factor of lung adenocarcinoma.
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Affiliation(s)
- Ji Zhu
- Department of Cardiothoracic Surgery, Changhai Hospital Affiliated to the Second Military Medical University, 168 Changhai Road, 200433, Shanghai, People's Republic of China
| | - Cong Wu
- Department of Laboratory Diagnosis, Changhai Hospital Affiliated to the Second Military Medical University, Shanghai, People's Republic of China
| | - Huafei Li
- International Joint Cancer Institute, Translational Medicine Research Institute, The Second Military Medical University, Shanghai, China
| | - Yang Yuan
- Department of Cardiothoracic Surgery, Changhai Hospital Affiliated to the Second Military Medical University, 168 Changhai Road, 200433, Shanghai, People's Republic of China
| | - Xiaotian Wang
- Department of Cardiothoracic Surgery, Changhai Hospital Affiliated to the Second Military Medical University, 168 Changhai Road, 200433, Shanghai, People's Republic of China
| | - Tiejun Zhao
- Department of Cardiothoracic Surgery, Changhai Hospital Affiliated to the Second Military Medical University, 168 Changhai Road, 200433, Shanghai, People's Republic of China.
| | - Jibin Xu
- Department of Cardiothoracic Surgery, Changzheng Hospital Affiliated to the Second Military Medical University, 415 Fengyang Road, 200433, Shanghai, People's Republic of China.
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Kim SH, Kaschula CH, Priedigkeit N, Lee AV, Singh SV. Forkhead Box Q1 Is a Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide. J Biol Chem 2016; 291:13495-508. [PMID: 27129776 PMCID: PMC4919436 DOI: 10.1074/jbc.m116.715219] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 04/29/2016] [Indexed: 11/06/2022] Open
Abstract
Diallyl trisulfide (DATS), a metabolic byproduct of garlic, is known to inhibit the growth of breast cancer cells in vitro and in vivo This study demonstrates that DATS targets breast cancer stem cells (bCSC). Exposure of MCF-7 and SUM159 human breast cancer cells to pharmacological concentrations of DATS (2.5 and 5 μm) resulted in dose-dependent inhibition of bCSC, as evidenced by a mammosphere assay and flow cytometric analysis of aldehyde dehydrogenase 1 (ALDH1) activity and the CD44(high)/CD24(low)/epithelial specific antigen-positive fraction. DATS-mediated inhibition of bCSC was associated with a decrease in the protein level of FoxQ1. Overexpression of FoxQ1 in MCF-7 and SUM159 cells increased ALDH1 activity and the CD49f(+)/CD24(-) fraction. Inhibition of ALDH1 activity and/or mammosphere formation upon DATS treatment was significantly attenuated by overexpression of FoxQ1. In agreement with these results, stable knockdown of FoxQ1 using small hairpin RNA augmented bCSC inhibition by DATS. Expression profiling for cancer stem cell-related genes suggested that FoxQ1 may negatively regulate the expression of Dachshund homolog 1 (DACH1), whose expression is lost in invasive breast cancer. Chromatin immunoprecipitation confirmed recruitment of FoxQ1 at the DACH1 promoter. Moreover, inducible expression of DACH1 augmented DATS-mediated inhibition of bCSC. Expression of FoxQ1 protein was significantly higher in triple-negative breast cancer cases compared with normal mammary tissues. Moreover, an inverse association was observed between FoxQ1 and DACH1 gene expression in breast cancer cell lines and tumors. DATS administration inhibited ALDH1 activity in vivo in SUM159 xenografts. These results indicate that FoxQ1 is a novel target of bCSC inhibition by DATS.
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Affiliation(s)
- Su-Hyeong Kim
- From the Department of Pharmacology and Chemical Biology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and
| | - Catherine H Kaschula
- the Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, South Africa
| | - Nolan Priedigkeit
- From the Department of Pharmacology and Chemical Biology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and
| | - Adrian V Lee
- From the Department of Pharmacology and Chemical Biology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and
| | - Shivendra V Singh
- From the Department of Pharmacology and Chemical Biology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and
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Let-7c blocks estrogen-activated Wnt signaling in induction of self-renewal of breast cancer stem cells. Cancer Gene Ther 2016; 23:83-9. [PMID: 26987290 DOI: 10.1038/cgt.2016.3] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Revised: 02/01/2016] [Accepted: 02/02/2016] [Indexed: 01/09/2023]
Abstract
Let-7 miRNAs are involved in carcinogenesis and tumor progression through their roles in maintaining differentiation and normal development. However, there is little research focusing on the effects of let-7 on Wnt-activated self-renewal of breast cancer stem cells. By analyzing the expression levels of let-7 family members in clinical tissues, we found that higher expression levels of let-7b and let-7c were correlated with better clinical prognosis of patients with estrogen receptor (ER)α-positive breast tumor. Further, we found that only let-7c was inversely correlated with ERα expression, and there is corelationship between let-7c and Wnt signaling in clinical tissues. Aldehyde dehydrogenase (ALDH)1 sorting and mammosphere formation assays showed that let-7c inhibited the self-renewal of stem cells in ERα-positive breast cancer. Let-7c decreased ERα expression through directly binding to the 3'UTR (untranslated region), and let-7c inhibited the estrogen-induced activation of Wnt signaling. Depletion of ERα abolished let-7c functions in stem cell signatures, which further confirmed that let-7c inhibited estrogen-induced Wnt activity through decreasing ERα expression. Taken together, our findings identified a biochemical and functional link between let-7c with ERα/Wnt signaling in breast cancer stem cells.
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Han N, Yuan X, Wu H, Xu H, Chu Q, Guo M, Yu S, Chen Y, Wu K. DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling. Oncotarget 2016; 6:5877-88. [PMID: 25788272 PMCID: PMC4467408 DOI: 10.18632/oncotarget.3463] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 01/22/2015] [Indexed: 11/25/2022] Open
Abstract
Whole-genome and transcriptome sequencing of non-small cell lung cancer (NSCLC) identified that DACH1, is a human homolog of drosophila gene dac, is involved in NSCLC. Here we showed that expression of DACH1 was significantly decreased in human NSCLC tissues and DACH1 abundance was inversely correlated with tumor stages and grades. Restoration of DACH1 expression in NSCLC cells significantly reduced cellular proliferation, clone formation, migration and invasion in vitro, as well as tumor growth in vivo. Unbiased screen and functional study suggested that DACH1 mediated effects were dependent in part on suppression of CXCL5. There was an inverse correlation between DACH1 mRNA levels and CXCL5 in both lung cancer cell lines and human NSCLC tissues. Kaplan-Mier analysis of human NSCLC samples demonstrated that high DACH1 mRNA levels predicted favorable prognosis for relapse-free and overall survival. In agreement, high CXCL5 expression predicted a worse prognosis for survival.
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Affiliation(s)
- Na Han
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Xun Yuan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Hua Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Hanxiao Xu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing, P.R. China
| | - Shiying Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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DACH1 is a novel predictive and prognostic biomarker in hepatocellular carcinoma as a negative regulator of Wnt/β-catenin signaling. Oncotarget 2016; 6:8621-34. [PMID: 25940701 PMCID: PMC4496171 DOI: 10.18632/oncotarget.3281] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 02/05/2015] [Indexed: 12/11/2022] Open
Abstract
The cell fate determination factor Dachshund (DACH1) functions as a novel suppressor in the progression of various neoplasms. Previous study has suggested that hypermethylation of promoter region was responsible for the reduction of DACH1 expression in hepatocellular carcinoma (HCC), and associated with the progression of HCC, but the clinical significance and the exact molecular mechanisms of DACH1 in the progression of HCC remain unclear. In this study, we employed public microarray data analysis and tissue microarrays (TMAs) technologies and showed that DACH1 expression was reduced in HCC even at early stage and associated with the tumor progression. Notably, Kaplan-Meier analysis further indicated DACH1 could be an independent prognostic factor for the overall survival of HCC. Further, mechanistic studies revealed that overexpression of DACH1 inhibited the growth and migration of HCC cell line, which were dependent in part on the inactivation of Wnt pathway via phosphorylation of GSK3β to suppress β-catenin. In agreement, the abundance of DACH1 was inversely correlated with several Wnt target genes. Collectively, our study indicated β-catenin is a novel target of DACH1 in HCC.
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Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis. Oncotarget 2016; 6:8525-38. [PMID: 25940700 PMCID: PMC4496164 DOI: 10.18632/oncotarget.3267] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 01/31/2015] [Indexed: 01/26/2023] Open
Abstract
Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1−/− mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1WT or cyclin D1KE in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1KE induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1WT and cyclin D1KE to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis.
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Regulation of Stem Cell Self-Renewal and Oncogenesis by RNA-Binding Proteins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 907:153-88. [PMID: 27256386 DOI: 10.1007/978-3-319-29073-7_7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Throughout their life span, multicellular organisms rely on stem cell systems. During development pluripotent embryonic stem cells give rise to all cell types that make up the organism. After birth, tissue stem cells maintain properly functioning tissues and organs under homeostasis as well as promote regeneration after tissue damage or injury. Stem cells are capable of self-renewal, which is the ability to divide indefinitely while retaining the potential of differentiation into multiple cell types. The ability to self-renew, however, is a double-edged sword; the molecular mechanisms of self-renewal can be a target of malignant transformation driving tumor development and progression. Growing lines of evidence have shown that RNA-binding proteins (RBPs) play pivotal roles in the regulation of self-renewal by modulating metabolism of coding and non-coding RNAs both in normal tissues and in cancers. In this review, we discuss our current understanding of tissue stem cell systems and how RBPs regulate stem cell fates as well as how the regulatory functions of RBPs contribute to oncogenesis.
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Abstract
Cells within the tumor are highly heterogeneous. Only a small portion of the cells within the tumor is capable to generate a new tumor. These cells are called cancer stem cells. Theoretically, cancer stem cells are originally from normal stem cells or early progenitor cells which accumulate the random mutations and undergo an altered version of the normal differentiation process. The cancer stem cell drives tumor progression and its recurrence. Thus, the technique to identify and purify the cancer stem cell is the key in any cancer stem cell research. In this protocol, we provide the basic technology of identification and purification of breast cancer stem cells as well as further functional assays to help the researchers achieve their research goals.
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Affiliation(s)
- Xuanmao Jiao
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, PA, 19107, USA
| | - Albert A Rizvanov
- Kazan Federal University, 18 Kremlyovskaya St, Kazan, Republic of Tatarstan, 420008, Russia
| | - Massimo Cristofanilli
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, PA, 19107, USA
| | - Regina R Miftakhova
- Kazan Federal University, 18 Kremlyovskaya St, Kazan, Republic of Tatarstan, 420008, Russia
| | - Richard G Pestell
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, PA, 19107, USA.
- Kazan Federal University, 18 Kremlyovskaya St, Kazan, Republic of Tatarstan, 420008, Russia.
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Du F, Yuan P, Wang T, Zhao J, Zhao Z, Luo Y, Xu B. The Significance and Therapeutic Potential of GATA3 Expression and Mutation in Breast Cancer: A Systematic Review. Med Res Rev 2015; 35:1300-15. [PMID: 26313026 DOI: 10.1002/med.21362] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/12/2015] [Accepted: 07/23/2015] [Indexed: 12/24/2022]
Affiliation(s)
- Feng Du
- Department of Medical Oncology, Cancer Hospital; Chinese Academy of Medical Sciences, Peking Union Medical College; Beijing 100021 China
| | - Peng Yuan
- Department of Medical Oncology, Cancer Hospital; Chinese Academy of Medical Sciences, Peking Union Medical College; Beijing 100021 China
| | - Teng Wang
- Tumor Marker Research Center, Cancer Institute and Hospital; Chinese Academy of Medical Sciences, Peking Union Medical College; Beijing 100191 China
| | - Jiuda Zhao
- Department of Medical Oncology, Cancer Hospital; Chinese Academy of Medical Sciences, Peking Union Medical College; Beijing 100021 China
| | - Zitong Zhao
- State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital; Chinese Academy of Medical Sciences, Peking Union Medical College; Beijing 100191 China
| | - Yang Luo
- Department of Medical Oncology, Cancer Hospital; Chinese Academy of Medical Sciences, Peking Union Medical College; Beijing 100021 China
| | - Binghe Xu
- Department of Medical Oncology, Cancer Hospital; Chinese Academy of Medical Sciences, Peking Union Medical College; Beijing 100021 China
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Curcumin Improves the Tumoricidal Effect of Mitomycin C by Suppressing ABCG2 Expression in Stem Cell-Like Breast Cancer Cells. PLoS One 2015; 10:e0136694. [PMID: 26305906 PMCID: PMC4549178 DOI: 10.1371/journal.pone.0136694] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 08/05/2015] [Indexed: 11/19/2022] Open
Abstract
Cancer cells with stem cell–like properties contribute to the development of resistance to chemotherapy and eventually to tumor relapses. The current study investigated the potential of curcumin to reduce breast cancer stem cell (BCSC) population for sensitizing breast cancer cells to mitomycin C (MMC) both in vitro and in vivo. Curcumin improved the sensitivity of paclitaxel, cisplatin, and doxorubicin in breast cancer cell lines MCF-7 and MDA-MB-231, as shown by the more than 2-fold decrease in the half-maximal inhibitory concentration of these chemotherapeutic agents. In addition, curcumin sensitized the BCSCs of MCF-7 and MDA-MB-231 to MMC by 5- and 15-fold, respectively. The BCSCs could not grow to the fifth generation in the presence of curcumin and MMC. MMC or curcumin alone only marginally reduced the BCSC population in the mammospheres; however, together, they reduced the BCSC population in CD44+CD24−/low cells by more than 75% (29.34% to 6.86%). Curcumin sensitized BCSCs through a reduction in the expression of ATP-binding cassette (ABC) transporters ABCG2 and ABCC1. We demonstrated that fumitremorgin C, a selective ABCG2 inhibitor, reduced BCSC survival to a similar degree as curcumin did. Curcumin sensitized breast cancer cells to chemotherapeutic drugs by reducing the BCSC population mainly through a reduction in the expression of ABCG2.
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Kellermayer Z, Hayasaka H, Kajtár B, Simon D, Robles EF, Martinez-Climent JA, Balogh P. Divergence of Vascular Specification in Visceral Lymphoid Organs-Genetic Determinants and Differentiation Checkpoints. Int Rev Immunol 2015; 35:489-502. [PMID: 26186200 DOI: 10.3109/08830185.2015.1059427] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Despite their functional similarities, peripheral lymphoid tissues are remarkably different according to their developmental properties and structural characteristics, including their specified vasculature. Access of leukocytes to these organs critically depends on their interactions with the local endothelium, where endothelial cells are patterned to display a restricted set of adhesion molecules and other regulatory compounds necessary for extravasation. Recent advances in high throughput analyses of highly purified endothelial subsets in various lymphoid tissues as well as the expansion of various transgenic animal models have shed new light on the transcriptional complexities of lymphoid tissue vascular endothelium. This review is aimed at providing a comprehensive analysis linking the functional competence of spleen and intestinal lymphoid tissues with the developmental programming and functional divergence of their vascular specification, with particular emphasis on the transcriptional control of endothelial cells exerted by Nkx2.3 homeodomain transcription factor.
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Affiliation(s)
- Zoltán Kellermayer
- a Department of Immunology and Biotechnology.,b Lymphoid Organogenesis Research Group Szentágothai Research Center, University of Pécs , Pécs , Hungary
| | - Haruko Hayasaka
- c Laboratory of Immunoregulation, Osaka University Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University , Osaka , Japan
| | - Béla Kajtár
- d Department of Pathology , University of Pécs , Pécs , Hungary
| | - Diána Simon
- a Department of Immunology and Biotechnology
| | - Eloy F Robles
- e Centro de Investigación Médica Aplicada of the University of Navarra , Pamplona , Spain
| | | | - Péter Balogh
- a Department of Immunology and Biotechnology.,b Lymphoid Organogenesis Research Group Szentágothai Research Center, University of Pécs , Pécs , Hungary
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46
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Liu Y, Han N, Zhou S, Zhou R, Yuan X, Xu H, Zhang C, Yin T, Wu K. The DACH/EYA/SIX gene network and its role in tumor initiation and progression. Int J Cancer 2015; 138:1067-75. [PMID: 26096807 DOI: 10.1002/ijc.29560] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 03/31/2015] [Indexed: 01/08/2023]
Abstract
The functional abnormality of developmental genes is a common phenomenon in cancer initiation and progression. The retinal determination gene network (RDGN) is a key signal in Drosophila eye specification, and this conservative pathway is also required for the development of multiple organs in mammalian species. Recent studies demonstrated that aberrant expressions of RDGN components in vertebrates, mainly Dach, Six, and Eya, represent a novel tumor signal. RDGN regulates proliferation, apoptosis, tumor growth and metastasis through interactions with multiple signaling pathways in a co-ordinated fashion; Dach acts as a tumor suppressor, whereas Six and Eya function as oncogenes. Clinical analyses demonstrated that the expression levels of RDGN correlate with tumor stage, metastasis and survival, suggesting that combinational detection of this pathway might be used as a promising biomarker for the stratification of therapy and for the prediction of the prognosis of cancer patients.
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Affiliation(s)
- Yu Liu
- Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Na Han
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Si Zhou
- Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Rong Zhou
- Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xun Yuan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Hanxiao Xu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Tiejun Yin
- Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Chen K, Wu K, Jiao X, Wang L, Ju X, Wang M, Di Sante G, Xu S, Wang Q, Li K, Sun X, Xu C, Li Z, Casimiro MC, Ertel A, Addya S, McCue PA, Lisanti MP, Wang C, Davis RJ, Mardon G, Pestell RG. The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a cxcl signaling module. Cancer Res 2015; 75:1992-2004. [PMID: 25769723 DOI: 10.1158/0008-5472.can-14-0611] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 02/24/2015] [Indexed: 01/01/2023]
Abstract
Prostate cancer is the second leading form of cancer-related death in men. In a subset of prostate cancer patients, increased chemokine signaling IL8 and IL6 correlates with castrate-resistant prostate cancer (CRPC). IL8 and IL6 are produced by prostate epithelial cells and promote prostate cancer cell invasion; however, the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein, the cell-fate determinant factor DACH1 inhibited CRPC tumor growth in mice. Using Dach1(fl/fl)/Probasin-Cre bitransgenic mice, we show IL8 and IL6 secretion was altered by approximately 1,000-fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to prostate epithelial cell growth and restrains migration via CXCL signaling. DACH1 inhibited expression, transcription, and secretion of the CXCL genes (IL8 and IL6) by binding to their promoter regulatory regions in chromatin. DACH1 is thus a newly defined determinant of benign and malignant prostate epithelium cellular growth, migration, and cytokine abundance in vivo.
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Affiliation(s)
- Ke Chen
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Kongming Wu
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
| | - Xuanmao Jiao
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Liping Wang
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Xiaoming Ju
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Min Wang
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Gabriele Di Sante
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Shaohua Xu
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Qiong Wang
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Kevin Li
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Xin Sun
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Congwen Xu
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Zhiping Li
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Mathew C Casimiro
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Adam Ertel
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Sankar Addya
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Peter A McCue
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Michael P Lisanti
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Chenguang Wang
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - Graeme Mardon
- Departments of Pathology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Richard G Pestell
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation.
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Brás-Pereira C, Casares F, Janody F. The retinal determination gene dachshund restricts cell proliferation by limiting the activity of the Homothorax-Yorkie complex. Development 2015; 142:1470-9. [DOI: 10.1242/dev.113340] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Accepted: 02/20/2015] [Indexed: 12/17/2022]
Abstract
The Drosophila transcriptional co-activator protein Yorkie and its vertebrate orthologs YAP and TAZ are potent oncogenes, whose activity is normally kept in check by the upstream Hippo kinase module. Upon its translocation into the nucleus, Yorkie forms complexes with several tissue-specific DNA-binding partners, which help to define the tissue-specific target genes of Yorkie. In the progenitor cells of the eye imaginal disc, the DNA-binding transcription factor Homothorax is required for Yorkie-promoted proliferation and survival through regulation of the bantam microRNA (miRNA). The transit from proliferating progenitors to cell cycle quiescent precursors is associated with the progressive loss of Homothorax and gain of Dachshund, a nuclear protein related to the Sno/Ski family of co-repressors. We have identified Dachshund as an inhibitor of Homothorax-Yorkie-mediated cell proliferation. Loss of dachshund induces Yorkie-dependent tissue overgrowth. Conversely, overexpressing dachshund inhibits tissue growth, prevents Yorkie or Homothorax-mediated cell proliferation of disc epithelia and restricts the transcriptional activity of the Yorkie-Homothorax complex on the bantam enhancer in Drosophila cells. In addition, Dachshund collaborates with the Decapentaplegic receptor Thickveins to repress Homothorax and Cyclin B expression in quiescent precursors. The antagonistic roles of Homothorax and Dachshund in Yorkie activity, together with their mutual repression, ensure that progenitor and precursor cells are under distinct proliferation regimes. Based on the crucial role of the human dachshund homolog DACH1 in tumorigenesis, our work suggests that DACH1 might prevent cellular transformation by limiting the oncogenic activity of YAP and/or TAZ.
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Affiliation(s)
- Catarina Brás-Pereira
- Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, Oeiras P-2780-156, Portugal
| | - Fernando Casares
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-UPO, Seville 41013, Spain
| | - Florence Janody
- Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, Oeiras P-2780-156, Portugal
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49
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Cohen H, Ben-Hamo R, Gidoni M, Yitzhaki I, Kozol R, Zilberberg A, Efroni S. Shift in GATA3 functions, and GATA3 mutations, control progression and clinical presentation in breast cancer. Breast Cancer Res 2014; 16:464. [PMID: 25410484 PMCID: PMC4303202 DOI: 10.1186/s13058-014-0464-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 10/14/2014] [Indexed: 02/03/2023] Open
Abstract
Introduction GATA binding protein 3 (GATA3) is a regulator of mammary luminal cell differentiation, and an estrogen receptor (ER) associated marker in breast cancer. Tumor suppressor functions of GATA3 have been demonstrated primarily in basal-like breast cancers. Here, we focused on its function in luminal breast cancer, where GATA3 is frequently mutated, and its levels are significantly elevated. Methods GATA3 target genes were identified in normal- and luminal cancer- mammary cells by ChIP-seq, followed by examination of the effects of GATA3 expressions and mutations on tumorigenesis-associated genes and processes. Additionally, mutations and expression data of luminal breast cancer patients from The Cancer Genome Atlas were analyzed to characterize genetic signatures associated with GATA3 mutations. Results We show that some GATA3 effects shift from tumor suppressing to tumor promoting during tumorigenesis, with deregulation of three genes, BCL2, DACH1, THSD4, representing major GATA3-controlled processes in cancer progression. In addition, we identify an altered activity of mutant GATA3, and distinct associated genetic signatures. These signatures depend on the functional domain mutated; and, for a specific subgroup, are shared with basal-like breast cancer patients, who are a clinical group with regard to considerations of mode of treatment. Conclusions The GATA3 dependent mechanisms may call for special considerations for proper prognosis and treatment of patients. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0464-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Helit Cohen
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, 52900, Israel.
| | - Rotem Ben-Hamo
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, 52900, Israel.
| | - Moriah Gidoni
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, 52900, Israel.
| | - Ilana Yitzhaki
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, 52900, Israel.
| | - Renana Kozol
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, 52900, Israel.
| | - Alona Zilberberg
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, 52900, Israel.
| | - Sol Efroni
- The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, 52900, Israel.
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Chu Q, Han N, Yuan X, Nie X, Wu H, Chen Y, Guo M, Yu S, Wu K. DACH1 inhibits cyclin D1 expression, cellular proliferation and tumor growth of renal cancer cells. J Hematol Oncol 2014; 7:73. [PMID: 25322986 PMCID: PMC4203876 DOI: 10.1186/s13045-014-0073-5] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 09/22/2014] [Indexed: 12/15/2022] Open
Abstract
Background Renal cell carcinoma (RCC) is a complex with diverse biological characteristics and distinct molecular signature. New target therapies to molecules that drive RCC initiation and progression have achieved promising responses in some patients, but the total effective rate is still far from satisfaction. Dachshund (DACH1) network is a key signaling pathway for kidney development and has recently been identified as a tumor suppressor in several cancer types. However, its role in renal cell carcinoma has not been fully investigated. Methods Immunohistochemical staining for DACH1, PCNA and cyclin D1 was performed on human renal tissue microaraays and correlation with clinic-pathological characteristics was analyzed. In vitro proliferation, apoptosis and in vivo tumor growth were evaluated on human renal cancer cell lines with decitabine treatment or ectopic expression of DACH1. Downstream targets and potential molecular mechanism were investigated through western blot, immunoprecipitation and reporter gene assays. Results Expression of DACH1 was significantly decreased in human renal carcinoma tissue. DACH1 protein abundance was inversely correlated with the expression of PCNA and cyclin D1, tumor grade, and TNM stage. Restoration of DACH1 function in renal clear cell cancer cells inhibited in vitro cellular proliferation, S phase progression, clone formation, and in vivo tumor growth. In mechanism, DACH1 repressed cyclin D1 transcription through association with AP-1 protein. Conclusion Our results indicated that DACH1 was a novel molecular marker of RCC and it attributed to the malignant behavior of renal cancer cells. Re-activation of DACH1 may represent a potential therapeutic strategy.
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Affiliation(s)
- Qian Chu
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Na Han
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Xun Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Xin Nie
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Hua Wu
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Yu Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853, China.
| | - Shiying Yu
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, China.
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