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Nothnick WB, Arachchige SP, Minchella P, Stephens EB, Graham A. Targeting c-MYC: a potential non-hormonal therapeutic approach for endometriosis treatment. Front Cell Dev Biol 2023; 11:1225055. [PMID: 38078012 PMCID: PMC10702580 DOI: 10.3389/fcell.2023.1225055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 11/01/2023] [Indexed: 01/23/2025] Open
Abstract
Endometriosis is a benign gynecological disease in which eutopic endometrial tissue composed of glands and stroma grow within the pelvic cavity. The disease affects females of reproductive age and is characterized by pelvic pain, infertility and reduced quality of life. The majority of pharmacologic treatment modalities for endometriosis focus on suppression of estradiol production and/or action; an approach associated with adverse side effects. c-MYC is elevated in eutopic endometrium and endometriotic lesion tissue in patients with endometriosis and the disease shares many similar pathological characteristics with that of endometrial carcinoma. While targeting of c-MYC with Omomyc has recently gained substantial interest in the field of cancer research, there has been no recent attempt to evaluate the potential utility in targeting c-MYC for endometriosis treatment. The following perspective article compares the similarities between endometriosis and endometrial cancer and presents preliminary data suggesting that targeting c-MYC with Omomyc reduces endometriotic cell proliferation and viability in vitro. Future application of targeting c-MYC in endometriosis treatment and potential pros and cons are then discussed.
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Affiliation(s)
- Warren B. Nothnick
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, United States
- Center for Reproductive Sciences, Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS, United States
| | - Sachith Polpitiya Arachchige
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Paige Minchella
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Edward B. Stephens
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Amanda Graham
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
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Transcriptome analysis of the ink sac and brain tissues from Sepiella inermis: A resource for discovering genes related to the inking of cephalopods. Mar Genomics 2022; 64:100968. [PMID: 35772238 DOI: 10.1016/j.margen.2022.100968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 06/09/2022] [Accepted: 06/17/2022] [Indexed: 11/23/2022]
Abstract
The common Chinese cuttlefish (Sepiella inermis) is an important cephalopod with nutritional and commercial value. Intensive inking stimulated by swilling seawater in transfer containers threatens the survival of cephalopods during transportation. However, the molecular basis for the inking behavior of S. inermis remains unclear. In the present study, transcriptome analysis was performed on ink sac and brain tissues from S. inermis under two different conditions, i.e. the control group (with individuals immersed in static seawater) and the experimental group (with individuals immersed in swilling seawater) to determine the global gene expression differences. The individuals from the experimental group ejected ink in response to the swilling of seawater. 330,699 unigenes were obtained from twelve transcriptome libraries via the Illumina Hiseq X platform, and the differentially expressed genes in the ink sac and brain tissues were identified respectively. Multiple upregulated genes in the ink sac were involved in cation transporter activity. Besides, an autocrine/paracrine factor wnt10b like and two important transcription factors (homeobox 1 and Hes-1-b-like) were also significantly upregulated in the ink sac. Moreover, a neuronal nitric oxide synthase (nNOS) was significantly downregulated in the brain. The findings from this study provide an important transcriptomic resource for discovering critical genes related to inking behavior of S. inermis, providing a basis for developing potential methods for protecting S. inermis from intensive inking.
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You GR, Chang JT, Li HF, Cheng AJ. Multifaceted and Intricate Oncogenic Mechanisms of NDRG1 in Head and Neck Cancer Depend on Its C-Terminal 3R-Motif. Cells 2022; 11:cells11091581. [PMID: 35563887 PMCID: PMC9104279 DOI: 10.3390/cells11091581] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
N-Myc downstream-regulated 1 (NDRG1) has inconsistent oncogenic functions in various cancers. We surveyed and characterized the role of NDRG1 in head and neck cancer (HNC). Cellular methods included spheroid cell formation, clonogenic survival, cell viability, and Matrigel invasion assays. Molecular techniques included transcriptomic profiling, RT-qPCR, immunoblotting, in vitro phosphorylation, immunofluorescent staining, and confocal microscopy. Prognostic significance was assessed by Kaplan–Meier analysis. NDRG1 participated in diverse oncogenic functions in HNC cells, mainly stress response and cell motility. Notably, NDRG1 contributed to spheroid cell growth, radio-chemoresistance, and upregulation of stemness-related markers (CD44 and Twist1). NDRG1 facilitated cell migration and invasion, and was associated with modulation of the extracellular matrix molecules (fibronectin, vimentin). Characterizing the 3R-motif in NDRG1 revealed its mechanism in the differential regulation of the phenotypes. The 3R-motif displayed minimal effect on cancer stemness but was crucial for cell motility. Phosphorylating the motif by GSK3b at serine residues led to its nuclear translocation to promote motility. Clinical analyses supported the oncogenic function of NDRG1, which was overexpressed in HNC and associated with poor prognosis. The data elucidate the multifaceted and intricate mechanisms of NDRG1 in HNC. NDRG1 may be a prognostic indicator or therapeutic target for refractory HNC.
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Affiliation(s)
- Guo-Rung You
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Joseph T. Chang
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 33302, Taiwan;
- School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Hsiao-Fan Li
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Ann-Joy Cheng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Department of Radiation Oncology and Proton Therapy Center, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 33302, Taiwan;
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Correspondence: ; Tel.: +886-3-211-8800
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Macsek P, Skoda J, Krchniakova M, Neradil J, Veselska R. Iron-Chelation Treatment by Novel Thiosemicarbazone Targets Major Signaling Pathways in Neuroblastoma. Int J Mol Sci 2021; 23:ijms23010376. [PMID: 35008802 PMCID: PMC8745636 DOI: 10.3390/ijms23010376] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 01/23/2023] Open
Abstract
Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.
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Affiliation(s)
- Peter Macsek
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Jan Skoda
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Maria Krchniakova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
| | - Jakub Neradil
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
- Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, 662 63 Brno, Czech Republic
- Correspondence: ; Tel.: +420-549-49-6003
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
- Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, 662 63 Brno, Czech Republic
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You GR, Chang JT, Li YL, Chen YJ, Huang YC, Fan KH, Chen YC, Kang CJ, Cheng AJ. Molecular Interplays Between Cell Invasion and Radioresistance That Lead to Poor Prognosis in Head-Neck Cancer. Front Oncol 2021; 11:681717. [PMID: 34307149 PMCID: PMC8299304 DOI: 10.3389/fonc.2021.681717] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
Background Cancer metastasis and recurrence after radiotherapy are the significant causes of poor prognosis in head-neck cancer (HNC). Clinically, it is commonly found that patients with either condition may accompany the outcome of the other. We hypothesized that HNC cells might exhibit a cross-phenotypic attribute between cell invasion and radioresistance. To discover effective biomarkers for the intervention of aggressive cancer at one time, the potential molecules that interplay between these two phenotypes were investigated. Materials and Methods Three isogenic HNC cell sublines with high invasion or radioresistance properties were established. Transcriptomic and bioinformatic methods were used to globally assess the phenotypic-specific genes, functional pathways, and co-regulatory hub molecules. The associations of gene expressions with patient survival were analyzed by Kaplan-Meier plotter, a web-based tool, using the HNSCC dataset (n=500). The molecular and cellular techniques, including RT-qPCR, flow cytometry, cell invasion assay, and clonogenic survival assay, were applied. Results The phenotypic crosstalk between cell invasion and radioresistance was validated, as shown by the existence of mutual properties in each HNC subline. A total of 695 genes was identified in associations with these two phenotypes, including 349 upregulated and 346 downregulated in HNC cells. The focal adhesion mechanism showed the most significant pathway to co-regulate these functions. In the analysis of 20 up-regulatory genes, a general portrait of correlative expression was found between these phenotypic cells (r=0.513, p=0.021), and nine molecules exhibited significant associations with poor prognosis in HNC patients (HR>1, p<0.050). Three hub genes were identified (ITGA6, TGFB1, and NDRG1) that represented a signature of interplayed molecules contributing to cell invasion, radioresistance and leading to poor prognosis. The ITGA6 was demonstrated as a prominent biomarker. The expression of ITGA6 correlated with the levels of several extracellular and apoptotic/anti-apoptotic molecules. Functionally, silencing ITGA6 suppressed cell migration, invasion, and attenuated radioresistance in HNC cells. Conclusions A panel of interplay molecules was identified that contribute to cell invasion and radioresistance, leading to poor prognosis. These panel molecules, such as ITGA6, may serve as predictive markers of radioresistance, prognostic markers of metastasis, and molecular therapeutic targets for refractory HNC.
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Affiliation(s)
- Guo-Rung You
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Joseph T Chang
- Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.,School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yan-Liang Li
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yin-Ju Chen
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan.,International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chen Huang
- Department of Oral Maxillofacial Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Kang-Hsing Fan
- Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.,Department of Radiation Oncology, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan.,Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yen-Chao Chen
- Department of Radiation Oncology, Chang Gung Memorial Hospital-Keelung, Keelung, Taiwan
| | - Chung-Jan Kang
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Otorhinolaryngology, Chang Gung Memorial Hospital-LinKou, Taoyuan, Taiwan
| | - Ann-Joy Cheng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Park KC, Paluncic J, Kovacevic Z, Richardson DR. Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer. Free Radic Biol Med 2020; 157:154-175. [PMID: 31132412 DOI: 10.1016/j.freeradbiomed.2019.05.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/24/2019] [Accepted: 05/16/2019] [Indexed: 12/18/2022]
Abstract
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that is regulated by hypoxia, metal ions including iron, the free radical nitric oxide (NO.), and various stress stimuli. This intriguing molecule exhibits diverse functions in cancer, inhibiting epithelial-mesenchymal transition (EMT), cell migration and angiogenesis by modulation of a plethora of oncogenes via cellular signaling. Thus, pharmacological targeting of NDRG1 signaling in cancer is a promising therapeutic strategy. Of note, novel anti-tumor agents of the di-2-pyridylketone thiosemicarbazone series, which exert the "double punch" mechanism by binding metal ions to form redox-active complexes, have been demonstrated to markedly up-regulate NDRG1 expression in cancer cells. This review describes the mechanisms underlying NDRG1 modulation by the thiosemicarbazones and the diverse effects NDRG1 exerts in cancer. As a major induction mechanism, iron depletion appears critical, with NO. also inducing NDRG1 through its ability to bind iron and generate dinitrosyl-dithiol iron complexes, which are then effluxed from cells. Apart from its potent anti-metastatic role, several studies have reported a pro-oncogenic role of NDRG1 in a number of cancer-types. Hence, it has been suggested that NDRG1 plays pleiotropic roles depending on the cancer-type. The molecular mechanism(s) underlying NDRG1 pleiotropy remain elusive, but are linked to differential regulation of WNT signaling and potentially differential interaction with the tumor suppressor, PTEN. This review discusses NDRG1 induction mechanisms by metal ions and NO. and both the anti- and possible pro-oncogenic functions of NDRG1 in multiple cancer-types and compares the opposite effects this protein exerts on cancer progression.
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Affiliation(s)
- Kyung Chan Park
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Jasmina Paluncic
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia
| | - Zaklina Kovacevic
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia.
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Medical Foundation Building (K25), The University of Sydney, Sydney, New South Wales, 2006, Australia.
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7
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Qu YH, Jian LY, Ce L, Ma Y, Xu CC, Gao YF, Machaty Z, Luo HL. Identification of candidate genes in regulation of spermatogenesis in sheep testis following dietary vitamin E supplementation. Anim Reprod Sci 2019; 205:52-61. [PMID: 31005359 DOI: 10.1016/j.anireprosci.2019.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 03/24/2019] [Accepted: 04/08/2019] [Indexed: 12/16/2022]
Abstract
Dietary vitamin E supplementation is beneficial to semen quality in different sheep and goat breeds. The aim of this research was to further investigate the effect of vitamin E in sheep on spermatogenesis and its regulatory mechanisms using RNA-seq. Thirty male Hu lambs were randomly divided into three groups. The animals received 0, 200 or 2000 IU/day vitamin E dietary supplementation for 105 days, and its effects were subsequently evaluated. The results indicate vitamin E supplementation increased the number of germ cells in the testes and epididymides. The positive effects were reduced, however, in animals that received 2000 IU/d vitamin E. Using the RNA-seq procedure, there was detection of a number of differentially expressed genes such as NDRG1, FSCN3 and CYP26B1 with these genes being mainly related to the regulation of spermatogenesis. Supplementation with 2000 IU/d vitamin E supplementation resulted in a lesser abundance of skeleton-related transcripts such as TUBB, VIM and different subtypes of collagen, and there was also an effect on the ECM-receptor interaction pathway. These changes appear to be responsible for the lesser beneficial effect of the greater vitamin E concentrations. The results provide a novel insight into the regulation of spermatogenesis by vitamin E at the molecular level, however, for a precise understanding of functions of the affected genes there needs to be further study.
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Affiliation(s)
- Yang-Hua Qu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
| | - Lu-Yang Jian
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
| | - Liu Ce
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
| | - Yong Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
| | - Chen-Chen Xu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
| | - Yue-Feng Gao
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
| | - Zoltan Machaty
- Purdue University, Department of Animal Sciences, West Lafayette, IN, 47907, USA.
| | - Hai-Ling Luo
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
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Wang H, Sun W, Sun M, Fu Z, Zhou C, Wang C, Zuo D, Zhou Z, Wang G, Zhang T, Xu J, Chen J, Wang Z, Yin F, Duan Z, Hornicek FJ, Cai Z, Hua Y. HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1. Biochim Biophys Acta Mol Basis Dis 2018. [PMID: 29524631 DOI: 10.1016/j.bbadis.2018.03.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. The abilities of chemotherapy resistance are major roadblock in the successful treatment of OS. The clarification of mechanism regarding cell survival during OS chemotherapy are important. Here, we examined HER4 expression by immunohistochemistry in a large series of OS tissues, and found HER4 expression correlated with tumor characteristics and patient survival rates. HER4 knockdown by shRNA inhibited OS cell growth and tumorigenesis, and induced cell senescence and apoptosis in vitro and in vivo. We demonstrated that HER4 expression upregulated in the adverse conditions, such as serum starvation and sphere culture. Moreover, HER4 knockdown cells became more sensitive in stressful conditions such as loss of attachment, cytotoxic agents or nutrition insufficiency. Mechanism studies revealed that HER4 interacted with NDRG1, and NDRG1 overexpression could antagonize HER4 knockdown-mediated cell growth and apoptosis in stressed conditions. There was a positive correlation between HER4 and NDRG1 immunoreactivity in OS patients. Together, our present study shows that HER4 and/or NDRG1 might play a critical role for the cell survival and chemo-resistance of OS, and could be used as potential therapeutic targets in OS.
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Affiliation(s)
- Hongsheng Wang
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China; Department of Orthopedics, Yangpu Hospital, Tongji University, Shanghai, China
| | - Wei Sun
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Mengxiong Sun
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Zeze Fu
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Chenghao Zhou
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Chongren Wang
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China
| | - Dongqing Zuo
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Zifei Zhou
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Gangyang Wang
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Tao Zhang
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Jing Xu
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Jian Chen
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Zhuoying Wang
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Fei Yin
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China
| | - Zhenfeng Duan
- Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, USA
| | - Francis J Hornicek
- Department of Orthopedic Surgery David Geffen School of Medicine at UCLA Los Angeles, USA
| | - Zhengdong Cai
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China.
| | - Yingqi Hua
- Department of Orthopedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China.
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The molecular effect of metastasis suppressors on Src signaling and tumorigenesis: new therapeutic targets. Oncotarget 2016; 6:35522-41. [PMID: 26431493 PMCID: PMC4742122 DOI: 10.18632/oncotarget.5849] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 08/15/2015] [Indexed: 02/07/2023] Open
Abstract
A major problem for cancer patients is the metastasis of cancer cells from the primary tumor. This involves: (1) migration through the basement membrane; (2) dissemination via the circulatory system; and (3) invasion into a secondary site. Metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade. Notably, Src is a non-receptor, cytoplasmic, tyrosine kinase, which becomes aberrantly activated in many cancer-types following stimulation of plasma membrane receptors (e.g., receptor tyrosine kinases and integrins). There is evidence of a prominent role of Src in tumor progression-related events such as the epithelial–mesenchymal transition (EMT) and the development of metastasis. However, the precise molecular interactions of Src with metastasis suppressors remain unclear. Herein, we review known metastasis suppressors and summarize recent advances in understanding the mechanisms of how these proteins inhibit metastasis through modulation of Src. Particular emphasis is bestowed on the potent metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1) and its interactions with the Src signaling cascade. Recent studies demonstrated a novel mechanism through which NDRG1 plays a significant role in regulating cancer cell migration by inhibiting Src activity. Moreover, we discuss the rationale for targeting metastasis suppressor genes as a sound therapeutic modality, and we review several examples from the literature where such strategies show promise. Collectively, this review summarizes the essential interactions of metastasis suppressors with Src and their effects on progression of cancer metastasis. Moreover, interesting unresolved issues regarding these proteins as well as their potential as therapeutic targets are also discussed.
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Chang X, Xu X, Xue X, Ma J, Li Z, Deng P, Chen J, Zhang S, Zhi Y, Dai D. NDRG1 Controls Gastric Cancer Migration and Invasion through Regulating MMP-9. Pathol Oncol Res 2016; 22:789-96. [PMID: 27154576 DOI: 10.1007/s12253-016-0071-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 04/27/2016] [Indexed: 01/16/2023]
Abstract
The purpose of this study is to detect the clinical significance of NDRG1 and its relationship with MMP-9 in gastric cancer metastatic progression. 101 cases of gastric cancer specimens were utilized to identify the protein expression of NDRG1 and MMP-9 by immunohistochemistry, their clinical significance was also analyzed. The suppression by siRNA-NDRG1 was employed to detect the role of NDRG1 in gastric cancer progression and its relationship with MMP-9. NDRG1 expression was correlated inversely with the degree of tumor cell differentiation (p < 0.01), invasion depth (p < 0.05), lymph node metastasis (p < 0.05) and TNM stage (p < 0.05), whereas MMP-9 was positive correlated with the degree of tumor cell differentiation (p < 0.01), lymph node metastasis (p < 0.05) and TNM stage (p < 0.05), but not correlated with invasion depth (p>0.05). Furthermore, cell proliferation and invasion effect were remarkably enhanced when NDRG1 was silencing, but MMP-9 expression was increased. NDRG1 silencing enhances gastric cancer cells progression through upregulating MMP-9. It suggests that NDRG1 may inhibit the metastasis of gastric cancer via regulating MMP-9.
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Affiliation(s)
- Xiaojing Chang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
- Department of Radiotherapy, The Second Hospital, Hebei Medical University, Shijiazhuang, China
| | - Xiaoyang Xu
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Xiaoying Xue
- Department of Radiotherapy, The Second Hospital, Hebei Medical University, Shijiazhuang, China
| | - Jinguo Ma
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Zhenhua Li
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Peng Deng
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Jing Chen
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Shuanglong Zhang
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Yu Zhi
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Dongqiu Dai
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.
- Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.
- Department of Gastrointestinal Surgery and Cancer Center, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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Baker AF, Malm SW, Pandey R, Laughren C, Cui H, Roe D, Chambers SK. Evaluation of a hypoxia regulated gene panel in ovarian cancer. CANCER MICROENVIRONMENT : OFFICIAL JOURNAL OF THE INTERNATIONAL CANCER MICROENVIRONMENT SOCIETY 2015; 8:45-56. [PMID: 25998313 PMCID: PMC4449346 DOI: 10.1007/s12307-015-0166-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 01/26/2015] [Indexed: 01/02/2023]
Abstract
A panel of nine hypoxia regulated genes, selected from a previously published fifty gene panel, was investigated for its ability to predict hypoxic ovarian cancer phenotypes. All nine genes including vascular endothelial growth factor A, glucose transporter 1, phosphoglycerate mutase 1, lactate dehydrogenase A, prolyl 4-hydroxylase, alpha-polypeptide 1, adrenomedullin, N-myc downstream regulated 1, aldolase A, and carbonic anhydrase 9 were upregulated in the HEY and OVCAR-3 human ovarian cell lines cultured in vitro under hypoxic compared to normoxic conditions as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The gene panel was also elevated in HEY xenograft tumor tissue compared to HEY cells cultured in normoxia. The HEY xenograft tissue demonstrated heterogeneous positive immunohistochemical staining for the exogenous hypoxia biomarker pimonidazole, and the hypoxia regulated protein carbonic anhydrase IX. A quantitative nuclease protection assay (qNPA) was developed which included the nine hypoxia regulated genes. The qNPA assay provided similar results to those obtained using qRT-PCR for cultured cell lines. The qNPA assay was also evaluated using paraffin embedded fixed tissues including a set of five patient matched primary and metastatic serous cancers and four normal ovaries. In this small sample set the average gene expression was higher in primary and metastatic cancer tissue compared to normal ovaries for the majority of genes investigated. This study supports further evaluation by qNPA of this gene panel as an alternative or complimentary method to existing protein biomarkers to identify ovarian cancers with a hypoxic phenotype.
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Affiliation(s)
- Amanda F. Baker
| | - Scott W. Malm
| | - Ritu Pandey
| | - Cindy Laughren
| | - Haiyan Cui
| | - Denise Roe
| | - Setsuko K. Chambers
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12
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Tang SC, Chen YC. Novel therapeutic targets for pancreatic cancer. World J Gastroenterol 2014; 20:10825-10844. [PMID: 25152585 PMCID: PMC4138462 DOI: 10.3748/wjg.v20.i31.10825] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/13/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.
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13
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Wang B, Li J, Ye Z, Li Z, Wu X. N-myc downstream regulated gene 1 acts as a tumor suppressor in ovarian cancer. Oncol Rep 2014; 31:2279-85. [PMID: 24626771 DOI: 10.3892/or.2014.3072] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Accepted: 02/14/2014] [Indexed: 12/12/2022] Open
Abstract
Although implicated in a number of tumor types, the role of N-myc downstream regulated gene 1 (NDRG1) in ovarian cancer (OC) is unclear. In the present study, we used short hairpin RNA (shRNA) to silence NDRG1 in the OC cell line OVCAR3 and assessed the effect of its knockdown on cell morphology, proliferation, colony formation, migration and invasion. To complement these knockdown studies, we overexpressed NDRG1 in the same cell line. We found that NDRG1 knockdown significantly enhanced OVCAR3 proliferation, migration and invasion; however, there were no apparent changes in cell morphology. We also examined the effect in vivo and found that NDRG1 depletion promoted OVCAR3 xenograft growth in nude mice. In accordance with these data, we found that NDRG1 overexpression decreased proliferation, adhesion and apoptosis, and induced G0/G1 cell cycle arrest in OVCAR3 cells; expression of p21 and p53 was also increased. In conclusion, we demonstrated that NDRG1 acts as a tumor suppressor in ovarian carcinogenesis and may be a potential therapeutic target in this disease.
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Affiliation(s)
- Bei Wang
- Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Jianli Li
- Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Zhanying Ye
- Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Zhe Li
- Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Xiaohua Wu
- Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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14
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Fang BA, Kovačević Ž, Park KC, Kalinowski DS, Jansson PJ, Lane DJR, Sahni S, Richardson DR. Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy. Biochim Biophys Acta Rev Cancer 2013; 1845:1-19. [PMID: 24269900 DOI: 10.1016/j.bbcan.2013.11.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 11/11/2013] [Accepted: 11/13/2013] [Indexed: 12/11/2022]
Abstract
N-myc down-regulated gene 1 (NDRG1) is a known metastasis suppressor in multiple cancers, being also involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses and immunity. In addition to its primary role as a metastasis suppressor, NDRG1 can also influence other stages of carcinogenesis, namely angiogenesis and primary tumour growth. NDRG1 is regulated by multiple effectors in normal and neoplastic cells, including N-myc, histone acetylation, hypoxia, cellular iron levels and intracellular calcium. Further, studies have found that NDRG1 is up-regulated in neoplastic cells after treatment with novel iron chelators, which are a promising therapy for effective cancer management. Although the pathways by which NDRG1 exerts its functions in cancers have been documented, the relationship between the molecular structure of this protein and its functions remains unclear. In fact, recent studies suggest that, in certain cancers, NDRG1 is post-translationally modified, possibly by the activity of endogenous trypsins, leading to a subsequent alteration in its metastasis suppressor activity. This review describes the role of this important metastasis suppressor and discusses interesting unresolved issues regarding this protein.
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Affiliation(s)
- Bernard A Fang
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia
| | - Žaklina Kovačević
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia
| | - Kyung Chan Park
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia
| | - Danuta S Kalinowski
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J Jansson
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia
| | - Darius J R Lane
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia
| | - Des R Richardson
- Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
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