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Histone Modifications Represent a Key Epigenetic Feature of Epithelial-to-Mesenchyme Transition in Pancreatic Cancer. Int J Mol Sci 2023; 24:ijms24054820. [PMID: 36902253 PMCID: PMC10003015 DOI: 10.3390/ijms24054820] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/25/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Pancreatic cancer is one of the most lethal malignant diseases due to its high invasiveness, early metastatic properties, rapid disease progression, and typically late diagnosis. Notably, the capacity for pancreatic cancer cells to undergo epithelial-mesenchymal transition (EMT) is key to their tumorigenic and metastatic potential, and is a feature that can explain the therapeutic resistance of such cancers to treatment. Epigenetic modifications are a central molecular feature of EMT, for which histone modifications are most prevalent. The modification of histones is a dynamic process typically carried out by pairs of reverse catalytic enzymes, and the functions of these enzymes are increasingly relevant to our improved understanding of cancer. In this review, we discuss the mechanisms through which histone-modifying enzymes regulate EMT in pancreatic cancer.
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Zhang W, Jiang T, Xie K. Epigenetic reprogramming in pancreatic premalignancy and clinical implications. Front Oncol 2023; 13:1024151. [PMID: 36874143 PMCID: PMC9978013 DOI: 10.3389/fonc.2023.1024151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 02/01/2023] [Indexed: 02/18/2023] Open
Abstract
Pancreatic cancer (PC) is the most lethal human cancer, with less than 10% 5-year survival. Pancreatic premalignancy is a genetic and epigenomic disease and is linked to PC initiation. Pancreatic premalignant lesions include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), with pancreatic acinar-to-ductal metaplasia (ADM) as the major source of pancreatic premalignant lesions. Emerging evidence reveals that an epigenetic dysregulation is an early event in pancreatic tumorigenesis. The molecular mechanisms of epigenetic inheritance include chromatin remodeling; modifications in histone, DNA, and RNA; non-coding RNA expression; and alternative splicing of RNA. Changes in those epigenetic modifications contribute to the most notable alterations in chromatin structure and promoter accessibility, thus leading to the silence of tumor suppressor genes and/or activation of oncogenes. The expression profiles of various epigenetic molecules provide a promising opportunity for biomarker development for early diagnosis of PC and novel targeted treatment strategies. However, how the alterations in epigenetic regulatory machinery regulate epigenetic reprogramming in pancreatic premalignant lesions and the different stages of their initiation needs further investigation. This review will summarize the current knowledge of epigenetic reprogramming in pancreatic premalignant initiation and progression, and its clinical applications as detection and diagnostic biomarkers and therapeutic targets in PC.
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Affiliation(s)
- Wei Zhang
- Center for Pancreatic Cancer Research, School of Medicine, The South China University of Technology, Guangzhou, China.,Department of Pathology, School of Medicine, The South China University of Technology, Guangzhou, China
| | - Tingting Jiang
- Center for Pancreatic Cancer Research, School of Medicine, The South China University of Technology, Guangzhou, China.,Department of Pathology, School of Medicine, The South China University of Technology, Guangzhou, China
| | - Keping Xie
- Center for Pancreatic Cancer Research, School of Medicine, The South China University of Technology, Guangzhou, China.,Department of Pathology, School of Medicine, The South China University of Technology, Guangzhou, China
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Xue J, Wu T, Huang C, Shu M, Shen C, Zheng B, Lv J. Identification of proline-rich protein 11 as a major regulator in mouse spermatogonia maintenance via an increase in BMI1 protein stability. Mol Biol Rep 2022; 49:9555-9564. [PMID: 35980531 DOI: 10.1007/s11033-022-07846-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/05/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND Spermatogenesis accompanied by self-renewal and differentiation of spermatogonia under complicated regulation is crucial for male fertility. Our previous study demonstrated that the loss of the B-lymphoma Mo-MLV insertion region 1 (BMI1) could cause male infertility and found a potential interaction between BMI1 and proline-rich protein 11 (PRR11); however, the specific co-regulatory effects of BMI1/PRR11 on spermatogonia maintenance remain unclear. METHODS AND RESULTS The expression of PRR11 was downregulated in a mouse spermatogonia cell line (GC-1) via transfection with PRR11-siRNAs, and PRR11 knockdown was verified by real-time reverse transcriptase polymerase chain reaction (RT-qPCR). The proliferative activity of GC-1 cells was determined using the cell counting kit (CCK-8), colony formation, and 5-ethynyl-2-deoxyuridine (EdU) incorporation assay. A Transwell assay was performed to evaluate the effects of PRR11 on GC-1 cell migration. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to measure GC-1 cell apoptosis. Furthermore, co-immunoprecipitation, RT-qPCR, and western blot analyses were used for investigating the regulatory mechanisms involved in this regulation. It was found that downregulation of PRR11 could cause a marked inhibition of proliferation and migration and induced apoptosis in GC-1 cells. Moreover, silencing of PRR11 obviously led to a reduction in the BMI1 protein level. PRR11 was found to interact with BMII at the endogenous protein level. PRR11 knockdown produced a decrease in BMI1 protein stability via an increase in BMI1 ubiquitination after which derepression in the transcription of protein tyrosine phosphatase receptor type M (Ptprm) occurred. Importantly, knockdown of Ptprm in PRR11-deficient GC-1 cells led to a reversal of proliferation and migration of GC-1 cells. CONCLUSIONS This study uncovered a novel mechanism by which PRR11 cooperated with BMI1 to facilitate GC-1 maintenance through targeting Ptprm. Our findings may provide a better understanding of the regulatory network in spermatogonia maintenance.
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Affiliation(s)
- Jiajia Xue
- Suzhou Dushu Lake Hospital (Dushu Lake Hospital Affiliated to Soochow University), Suzhou, 215124, China
| | - Tiantian Wu
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, 215002, China
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Chao Huang
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, 215002, China
| | - Minghua Shu
- Suzhou Dushu Lake Hospital (Dushu Lake Hospital Affiliated to Soochow University), Suzhou, 215124, China
| | - Cong Shen
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, 215002, China
| | - Bo Zheng
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, 215002, China.
| | - Jinxing Lv
- Suzhou Dushu Lake Hospital (Dushu Lake Hospital Affiliated to Soochow University), Suzhou, 215124, China.
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Xu J, Li L, Shi P, Cui H, Yang L. The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies. Int J Mol Sci 2022; 23:ijms23158231. [PMID: 35897796 PMCID: PMC9367737 DOI: 10.3390/ijms23158231] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 12/01/2022] Open
Abstract
B-cell-specific Moloney murine leukemia virus integration region 1 (Bmi-1, also known as RNF51 or PCGF4) is one of the important members of the PcG gene family, and is involved in regulating cell proliferation, differentiation and senescence, and maintaining the self-renewal of stem cells. Many studies in recent years have emphasized the role of Bmi-1 in the occurrence and development of tumors. In fact, Bmi-1 has multiple functions in cancer biology and is closely related to many classical molecules, including Akt, c-MYC, Pten, etc. This review summarizes the regulatory mechanisms of Bmi-1 in multiple pathways, and the interaction of Bmi-1 with noncoding RNAs. In particular, we focus on the pathological processes of Bmi-1 in cancer, and explore the clinical relevance of Bmi-1 in cancer biomarkers and prognosis, as well as its implications for chemoresistance and radioresistance. In conclusion, we summarize the role of Bmi-1 in tumor progression, reveal the pathophysiological process and molecular mechanism of Bmi-1 in tumors, and provide useful information for tumor diagnosis, treatment, and prognosis.
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Affiliation(s)
- Jie Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Lin Li
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
| | - Pengfei Shi
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
- Correspondence: (H.C.); (L.Y.)
| | - Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, China; (J.X.); (L.L.); (P.S.)
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
- Correspondence: (H.C.); (L.Y.)
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Wu S, Zhang H, Gao C, Chen J, Li H, Meng Z, Bai J, Shen Q, Wu H, Yin T. Hyperglycemia Enhances Immunosuppression and Aerobic Glycolysis of Pancreatic Cancer Through Upregulating Bmi1-UPF1-HK2 Pathway. Cell Mol Gastroenterol Hepatol 2022; 14:1146-1165. [PMID: 35863742 PMCID: PMC9606831 DOI: 10.1016/j.jcmgh.2022.07.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/09/2022] [Accepted: 07/11/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Accumulating evidence strongly suggests that hyperglycemia promotes the progression of pancreatic cancer (PC). Approximately 80% of patients with PC are intolerant to hyperglycemic conditions. In this study, we define the role of Bmi1, a stemness-related oncogene, in controlling the Warburg effect, and immune suppression under hyperglycemia conditions. METHODS The diabetes mellitus model was established by intraperitoneal injection of streptozotocin. The role of the hyperglycemia-Bmi1-HK2 axis in glycolysis-related immunosuppression was examined in both orthotopic and xenograft in vivo models. Evaluation of immune infiltrates was carried out by flow cytometry. Human PC cell lines, SW1990, BxPC-3, and CFPAC-1, were used for mechanistic in vitro studies. RESULTS Through bioinformatics analysis, we found that hyperglycemia was strongly related to aerobic glycolysis, immunosuppression, and cancer cell stemness. High glucose condition in the tumor microenvironment promotes immune suppression by upregulating glycolysis in PC cells, which can be rescued via knockdown Bmi1 expression or after 2-deoxy-D-glucose treatment. Through gain-/loss-of-function assessments, we found that Bmi1 upregulated the expression of UPF1, which enhanced the stability of HK2 mRNA and thereby increased the expression of HK2. The role of the hyperglycemia-Bmi-HK2 pathway in the inhibition of antitumor immunity was further verified via the immune-competent and immunodeficient mice model. We also demonstrated that hyperglycemia promotes the expression of Bmi1 by elevating the intracellular acetyl-CoA levels and histone H4 acetylation levels. CONCLUSIONS Our results suggest that the previously unreported Bmi1-UPF1-HK2 pathway contributes to PC progression and immunosuppression, which may bring in new targets for developing effective therapies to treat patients with PC.
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Affiliation(s)
- Shihong Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haoxiang Zhang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenggang Gao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaoshun Chen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hehe Li
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zibo Meng
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany
| | - Jianwei Bai
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiang Shen
- Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Correspondence Address correspondence to: Tao Yin, MD, PhD, Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Tel: +86 027-85351631.
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Carrasco-Garcia E, Lopez L, Moncho-Amor V, Carazo F, Aldaz P, Collado M, Bell D, Gaafar A, Karamitopoulou E, Tzankov A, Hidalgo M, Rubio Á, Serrano M, Lawrie CH, Lovell-Badge R, Matheu A. SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression. Cancers (Basel) 2022; 14:cancers14040916. [PMID: 35205666 PMCID: PMC8870732 DOI: 10.3390/cancers14040916] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Pancreatic cancers are lethal types of cancer. A majority of patients progress to an advanced and metastatic disease, which remains a major clinical problem. Therefore, it is crucial to identify critical regulators to help predict the disease progression and to develop more efficacious therapeutic approaches. In this work we found that an increased expression of the developmental factor SOX9 is associated with metastasis, a poor prognosis and resistance to therapy in pancreatic ductal adenocarcinoma patients and in cell cultures. We also found that this effect is at least in part due to the ability of SOX9 to regulate the activity of stem cell factors, such as BMI1, in addition to those involved in EMT and metastasis. Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer. Methods: We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies. Results: Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in K-Ras transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression. Conclusions: Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.
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Affiliation(s)
- Estefania Carrasco-Garcia
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- Correspondence: (E.C.-G.); (A.M.); Tel.: +34-943-006073 (E.C.-G. & A.M.); Fax: +34-943-006250 (E.C.-G. & A.M.)
| | - Lidia Lopez
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
| | - Veronica Moncho-Amor
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
- The Francis Crick Institute, London NW1 1AT, UK; (D.B.); (R.L.-B.)
| | - Fernando Carazo
- School of Engineering, University of Navarra, 20009 San Sebastian, Spain; (F.C.); (Á.R.)
| | - Paula Aldaz
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
| | - Manuel Collado
- Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), 15706 Santiago de Compostela, Spain;
| | - Donald Bell
- The Francis Crick Institute, London NW1 1AT, UK; (D.B.); (R.L.-B.)
| | - Ayman Gaafar
- Department of Pathology, Cruces University Hospital, 48903 Barakaldo, Spain;
| | | | - Alexandar Tzankov
- Institute of Pathology, University Hospital Basel, 4056 Basel, Switzerland;
| | - Manuel Hidalgo
- Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain;
- New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY 10065, USA
| | - Ángel Rubio
- School of Engineering, University of Navarra, 20009 San Sebastian, Spain; (F.C.); (Á.R.)
| | - Manuel Serrano
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain;
- Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
| | - Charles H. Lawrie
- Molecular Oncology Group, Biodonostia Institute, 20014 San Sebastian, Spain;
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | | | - Ander Matheu
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (L.L.); (V.M.-A.); (P.A.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- Correspondence: (E.C.-G.); (A.M.); Tel.: +34-943-006073 (E.C.-G. & A.M.); Fax: +34-943-006250 (E.C.-G. & A.M.)
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Thompson JK, Bednar F. Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma. EPIGENOMES 2021; 5:20. [PMID: 34968245 PMCID: PMC8715475 DOI: 10.3390/epigenomes5040020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor's intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic approaches in this deadly cancer.
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Affiliation(s)
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA;
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Tan M, Meng J, Sun X, Fu X, Wang R. EPS8 supports pancreatic cancer growth by inhibiting BMI1 mediated proteasomal degradation of ALDH7A1. Exp Cell Res 2021; 407:112782. [PMID: 34391775 DOI: 10.1016/j.yexcr.2021.112782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/11/2021] [Accepted: 07/17/2021] [Indexed: 01/29/2023]
Abstract
Aldehyde dehydrogenase 7 family member A1 (ALDH7A1) is an enzyme catalyzing lipid peroxidation of fatty aldehydes. It plays a critical role in sustaining high oxygen consumption rate (OCR) and ATP production in pancreatic ductal adenocarcinoma (PADC). However, why PADC cells maintain a relatively high level of ALDH7A1 concentration is still not well understood. In the current study, we explored the interplay between epidermal growth factor receptor kinase substrate 8 (EPS8) and ALDH7A1 in PADC cells. PADC cell lines MIA PaCa-2 and AsPANC-1 were used for in vitro and in vivo studies. The co-IP assay showed mutual interactions between Flag-EPS8 and Myc-ALDH7A1 in both MIA PaCa-2 and AsPANC-1 cells. EPS8 knockdown resulted in decreased ALDH7A1 protein levels and increased poly-ubiquitination. An interaction was observed between ALDH7A1 and BMI1 but not between BMI1 and EPS8. BMI1 knockdown reduced ALDH7A1 poly-ubiquitination and degradation caused by EPS8 knockdown. Dual EPS8 and ALDH7A1 knockdown had a synergistic effect on suppressing PADC cell proliferation in vitro and in vivo. In conclusion, this study revealed that EPS8 supports PADC growth by interacting with ALDH7A1 and inhibiting BMI1 mediated proteasomal degradation of ALDH7A1.
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Affiliation(s)
- Mingzhu Tan
- Internal Medicine, Weifang People's Hospital Brain Hospital, Weifang, Shandong, 261000, China
| | - Jun Meng
- Occupational Medicine, Weifang People's Hospital, Weifang, Shandong, 261000, China
| | - Xiaojuan Sun
- Occupational Medicine, Weifang People's Hospital, Weifang, Shandong, 261000, China
| | - Xiaowei Fu
- Department of Neonatology, Weifang People's Hospital, Weifang, Shandong, 261000, China
| | - Ruihao Wang
- Internal Medicine, Weifang People's Hospital Brain Hospital, Weifang, Shandong, 261000, China.
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9
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The role of SOX family transcription factors in gastric cancer. Int J Biol Macromol 2021; 180:608-624. [PMID: 33662423 DOI: 10.1016/j.ijbiomac.2021.02.202] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/26/2021] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is a leading cause of death worldwide. GC is the third-most common cause of cancer-related death after lung and colorectal cancer. It is also the fifth-most commonly diagnosed cancer. Accumulating evidence has revealed the role of signaling networks in GC progression. Identification of these molecular pathways can provide new insight into therapeutic approaches for GC. Several molecular factors involved in GC can play both onco-suppressor and oncogene roles. Sex-determining region Y (Sry)-box-containing (SOX) family members are transcription factors with a well-known role in cancer. SOX proteins can bind to DNA to regulate cellular pathways via a highly conserved domain known as high mobility group (HMG). In the present review, the roles of SOX proteins in the progression and/or inhibition of GC are discussed. The dual role of SOX proteins as tumor-promoting and tumor-suppressing factors is highlighted. SOX members can affect upstream mediators (microRNAs, long non-coding RNAs and NF-κB) and down-stream mediators (FAK, HIF-1α, CDX2 and PTEN) in GC. The possible role of anti-tumor compounds to target SOX pathway members in GC therapy is described. Moreover, SOX proteins may be used as diagnostic or prognostic biomarkers in GC.
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Yu J, Chen L, Bao Z, Liu Y, Liu G, Li F, Li L. BMI‑1 promotes invasion and metastasis in endometrial adenocarcinoma and is a poor prognostic factor. Oncol Rep 2020; 43:1630-1640. [PMID: 32323819 PMCID: PMC7108087 DOI: 10.3892/or.2020.7539] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 02/12/2020] [Indexed: 12/31/2022] Open
Abstract
Endometrial adenocarcinoma is one of the most common types of gynecological malignancies and its incidence and mortality rates are increasing. Due to tumor recurrence and metastasis, the overall five-year survival rate of patients with endometrial adenocarcinoma is shortened. The aim of the present was to investigate the role of the polycomb group protein B-lymphoma Mo-MLV insertion region 1 (BMI-1) in the invasion, metastasis and the epithelial-mesenchymal transition (EMT) of endometrial adenocarcinoma cells, as well its effects on the prognosis of patients with endometrial adenocarcinoma. Immunohistochemistry was used to examine the expression profile of BMI-1 in normal and endometrial adenocarcinoma tissues. Western blotting was used to examine the expression levels of BMI-1 and EMT markers. Kaplan-Meier plots and a Cox proportional hazards model were used to assess the overall survival. MTT cell viability assays were used to detect the proliferation of endometrial cancer cells. Transwell assays were used to examine cell migration and invasion. Small interfering RNA was used to downregulate BMI-1 expression levels, to study its effect on EMT. Immunohistochemical and clinicopathological analyses showed that BMI-1 expression was increased in endometrial adenocarcinoma tissue compared with the normal endometrial tissue (P<0.05). The increased expression levels of BMI-1 were closely associated with stage, myometrial invasion and lymph node metastasis (P<0.05). Kaplan-Meier plots and a Cox proportional hazards model showed that increased BMI-1 expression was associated with a less favorable prognosis [P=0.040, hazards ratio (HR)=1.596] and was associated with late-stage adenocarcinoma (P=0.006, HR=1.670). Myometrial invasion (P=0.006, HR=1.509) and lymph node metastasis (P=0.004, HR=1.703) were determined to predict a less favorable prognosis. Downregulation of BMI-1 reduced migration and invasion in endometrial cancer cells in vivo. It was also found that downregulation of BMI-1 increased the expression levels of the epithelial markers E-cadherin and keratin, and decreased the expression levels of the mesenchymal markers N-cadherin, vimentin and the downstream transcription factor, Slug. In conclusion, BMI-1 expression was correlated with tumor invasion and metastasis, contributing to deep myometrial invasion and lymph node metastasis, and was a poor prognostic factor for endometrial adenocarcinoma.
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Affiliation(s)
- Jing Yu
- Department of Pathology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Ling Chen
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang 832001, P.R. China
| | - Zhenhua Bao
- Department of Oncology, People's Hospital of Haiyang, Haiyang, Shandong 265100, P.R. China
| | - Ying Liu
- Department of Physical Examination, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Guohong Liu
- Department of Obstetrics and Gynecology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Fengling Li
- Department of Obstetrics and Gynecology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Lianqin Li
- Department of Obstetrics and Gynecology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
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11
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Aldaz P, Otaegi-Ugartemendia M, Saenz-Antoñanzas A, Garcia-Puga M, Moreno-Valladares M, Flores JM, Gerovska D, Arauzo-Bravo MJ, Samprón N, Matheu A, Carrasco-Garcia E. SOX9 promotes tumor progression through the axis BMI1-p21 CIP. Sci Rep 2020; 10:357. [PMID: 31941916 PMCID: PMC6962164 DOI: 10.1038/s41598-019-57047-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/20/2019] [Indexed: 12/14/2022] Open
Abstract
The developmental regulator SOX9 is linked to cancer progression mainly as a result of its role in the regulation of cancer stem cells (CSCs). However, its activity in the differentiated cells that constitute the heterogeneous tumor bulk has not been extensively studied. In this work, we addressed this aspect in gastric cancer, glioblastoma and pancreatic adenocarcinoma. SOX9 silencing studies revealed that SOX9 is required for cancer cell survival, proliferation and evasion of senescence in vitro and tumor growth in vivo. Gain of-SOX9 function showed that high levels of SOX9 promote tumor cell proliferation in vitro and in vivo. Mechanistically, the modulation of SOX9 changed the expression of the transcriptional repressor BMI1 in the same direction in the three types of cancer, and the expression of the tumor suppressor p21CIP in the opposite direction. In agreement with this, SOX9 expression positively correlated with BMI1 levels and inversely with p21CIP in clinical samples of the different cancers. Moreover, BMI1 re-establishment in SOX9-silenced tumor cells restored cell viability and proliferation as well as decreased p21CIPin vitro and tumor growth in vivo. These results indicate that BMI1 is a critical effector of the pro-tumoral activity of SOX9 in tumor bulk cells through the repression of p21CIP. Our results highlight the relevance of the SOX9-BMI1-p21CIP axis in tumor progression, shedding novel opportunities for therapeutic development.
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Affiliation(s)
- Paula Aldaz
- Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain
| | | | | | - Mikel Garcia-Puga
- Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain
| | - Manuel Moreno-Valladares
- Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain.,Donostia Hospital, San Sebastian, Spain
| | - Juana M Flores
- Department of Animal Medicine and Surgery, Complutense University of Madrid, Madrid, Spain
| | - Daniela Gerovska
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, San Sebastian, Spain
| | - Marcos J Arauzo-Bravo
- Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, San Sebastian, Spain.,CIBERfes, Madrid, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Nicolas Samprón
- Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain.,Donostia Hospital, San Sebastian, Spain.,CIBERfes, Madrid, Spain
| | - Ander Matheu
- Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. .,CIBERfes, Madrid, Spain. .,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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12
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Rao RS, Raju K L, Augustine D, Patil S. Prognostic Significance of ALDH1, Bmi1, and OCT4 Expression in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma. Cancer Control 2020; 27:1073274820904959. [PMID: 32951453 PMCID: PMC7791458 DOI: 10.1177/1073274820904959] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/18/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Increasing evidence suggests the involvement of cancer stem cells (CSCs) in both oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Among the various CSC markers, aldehyde dehydrogenase (ALDH) 1, B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1), and octamer-binding protein 4 (OCT4) have been noted to increase in OSCC. The aim of the study was to analyze ALDH1, Bmi1, and OCT4 expression in OED and OSCC with clinicopathologic correlation and survival analysis. METHODS A total of 40 cases each of OED and OSCC were retrieved from departmental archives. Expression of ALDH1, Bmi1, and OCT4 was analyzed using immunohistochemistry and was correlated with clinicopathological parameters. A follow-up ranging from 6 to 52 months was considered for Kaplan-Meier survival analysis. The log-rank test was performed to analyze significant difference in survival rates. RESULTS The expression levels of ALDH1, Bmi1, and OCT4 increased significantly from OED through OSCC (P < .05). The expression of ALDH1 and OCT4 showed a significant correlation with lymph node metastasis. Positive cases of ALDH1 showed a significantly reduced survival rate compared to cases showing negative expression. Kaplan-Meier survival analysis showed a significant reduction of survival rate (P = .00) in patients showing a positive expression for all the 3 markers. CONCLUSION ALDH1 and OCT4 could be used as individual prognostic markers for assessing prognosis. ALDH1, Bmi1, and OCT4 could be used as a collective panel of markers to enable surgeons in predicting the prognosis of patients and thereby carry out prompt follow-up for such cases.
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Affiliation(s)
- Roopa S. Rao
- Department of Oral Pathology and Microbiology, Faculty of Dental
Sciences, M.S. Ramaiah University of Applied
Sciences, India
| | - Lizbeth Raju K
- Department of Oral Pathology and Microbiology, Faculty of Dental
Sciences, M.S. Ramaiah University of Applied
Sciences, India
| | - Dominic Augustine
- Department of Oral Pathology and Microbiology, Faculty of Dental
Sciences, M.S. Ramaiah University of Applied
Sciences, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, College
of Dentistry, Jazan University, Saudi Arabia
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13
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Kowolik CM, Lin M, Xie J, Overman LE, Horne DA. Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:431. [PMID: 31661013 PMCID: PMC6819529 DOI: 10.1186/s13046-019-1445-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 10/10/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer. METHODS We characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo. RESULTS NT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine. CONCLUSIONS Favorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease.
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Affiliation(s)
- Claudia M Kowolik
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Min Lin
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Jun Xie
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Larry E Overman
- Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA, 92697-2025, USA
| | - David A Horne
- Department of Molecular Medicine, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
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14
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Li Q, Li S, Yang X, Zhang X, Song C, Zhu S. Association between RNF2+P-AKT expression in pretreatment biopsy specimens, and poor survival following radiotherapy in patients with esophageal squamous cell carcinoma. Oncol Lett 2019; 18:3734-3742. [PMID: 31516586 PMCID: PMC6732994 DOI: 10.3892/ol.2019.10727] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 07/09/2019] [Indexed: 12/13/2022] Open
Abstract
The protein expression levels of Ring finger protein 2 (RNF2) and phosphor-protein kinase B (P-AKT) were determined in esophageal squamous cell carcinoma (ESCC) tissues, and the association between patient clinicopathological characteristics and survival time following definitive intensity-modulated radiotherapy was assessed. Cancerous biopsy tissues were collected from patients with ESCC at The Fourth Affiliated Hospital of Hebei Medical University between January 2010 and December 2013. Of these 99 cases, 83 were used to analyze the protein expression level of RNF2 (89.2% positive), 85 for P-AKT (65.9% positive) and 80 for RNF2+P-AKT protein expression levels (62.5% both positive). The expression levels of RNF2 protein in ESCC were associated with tumor volume (P=0.024), whilst those of P-AKT and RNF2+PAKT were associated with sex (P=0.041 and P=0.003, respectively). There were no significant differences in overall survival (OS) or progression-free survival (PFS) rate between the RNF2- and the RNF2+-+++ groups (P=0.134 and P=0.366, respectively), or between the P-AKT- group and P-AKT+-+++ group (P=0.468; P=0.580, respectively). The 1-, 3- and 5-year OS rates were 68.0, 28.0, and 20.0%, and 86.7, 53.3, and 31.1%, in the RNF2/P-AKT+ group and Other group, respectively (χ2=4.205; P=0.040). Multivariate analysis revealed that age, T stage and RNF2+P-AKT expression were independent prognostic factors for ESCC (P=0.010, P=0.008 and P=0.010, respectively). The expression of RNF2+P-AKT combined was an independent prognostic factor affecting survival rate, and therefore presents a potential prognostic indicator for patients with ESCC, treated with definitive radiotherapy.
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Affiliation(s)
- Qiaofang Li
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.,Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China
| | - Shuguang Li
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xingxiao Yang
- Department of Infectious Disease, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xueyuan Zhang
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Chunyang Song
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Shuchai Zhu
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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15
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Wu J, Liu L, Jin H, Li Q, Wang S, Peng B. LncSNHG3/miR-139-5p/BMI1 axis regulates proliferation, migration, and invasion in hepatocellular carcinoma. Onco Targets Ther 2019; 12:6623-6638. [PMID: 31692508 PMCID: PMC6708045 DOI: 10.2147/ott.s196630] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 01/25/2019] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE Emerging evidence has revealed that lncRNA small nucleolar RNA host gene 3 (SNHG3) is involved in cell proliferation, migration, and invasion in various tumors. However, the underlying molecular mechanism of SNHG3 in hepatocellular carcinoma (HCC) is still not fully explored. METHODS Quantitative reverse transcriptase PCR was employed to detect the expression of SNHG3, miR-139-5p, and BMI1. Colony assay and MTT assay were used to detect the proliferation. Transwell assay was introduced to measure the migration and invasion ability. Bioinformatics analysis and luciferase reporter assay were used to confirm the relationship between SNHG3, miR-139-5p, and BMI1. An animal experiment was adopted to detect the function of SNHG3 in vivo. RESULTS SNHG3 and BMI1 were upregulated in HCC, while miR-139-5p was downregulated. Knockdown of SNHG3 or BMI1 and overexpression of miR-139-5p could inhibit cell proliferation, migration, and invasion in HCC. miR-139-5p was a target of SNHG3 and BMI1 was a direct target mRNA of miR-139-5p. Silencing SNHG3 could impair the tumor progression in vivo. CONCLUSION The lncRNA SNHG3/miR-139-5p/BMI1 axis plays an important role in cell proliferation, migration, and invasion in HCC.
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Affiliation(s)
- Jian Wu
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Lingyun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China
| | - Huilin Jin
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Qiao Li
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Shutong Wang
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Baogang Peng
- Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China
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16
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Li H, Zhang Z, Gao C, Wu S, Duan Q, Wu H, Wang C, Shen Q, Yin T. Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells. Cell Biosci 2019; 9:50. [PMID: 31244991 PMCID: PMC6582499 DOI: 10.1186/s13578-019-0312-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 06/14/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. However, its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. A strategy of combined chemo-regimens is widely employed in clinical settings in attempt to reduce the chance of developing therapeutic resistance. Valproic acid (VPA) has been reported as a promising anticancer drug in various clinical trials and studies. However, the clinical value and potential dose-effect of VPA in combination with gemcitabine for pancreatic cancer treatment are under investigated. RESULTS In this study, we determined the synergistic effect of VPA and gemcitabine and found that high-dose VPA significantly and dose-dependently enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Intriguingly, low-dose VPA potentiated the migration and invasion of pancreatic cancer cells that already showed gemcitabine-induced motility. Moreover, low-dose VPA increased the reactive oxygen species (ROS) production, which activated AKT to further stimulate the activation of STAT3, Bmi1 expression and eventually promoted the migration and invasion of pancreatic cancer cells induced by gemcitabine. Whereas high-dose VPA stimulated excessive ROS accumulation that promoted p38 activation, which suppressed the activation of STAT3 and Bmi1. CONCLUSION Pancreatic cancer cells respond differentially towards low- or high-dose of VPA in combination with gemcitabine, and a low VPA further potentiate pancreatic cancer cell to migrate and invade. Our results suggest that STAT3/Bmi1 signaling cascade, which is regulated by ROS-dependent, AKT- or p38-modulated pathways, primarily mediated the sensitivity and motility of pancreatic cancer cells towards combined gemcitabine and VPA regimen. These findings suggest a highly clinically relevant new mechanism of developing resistance against combined chemo-regimens, warranting further mechanistic and translational exploration for VPA in combination with gemcitabine and other chemotherapies.
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Affiliation(s)
- Hehe Li
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Zhengle Zhang
- Department of Pancreatic Surgery, Renmin Hospital, Wuhan University, Wuhan, 430060 China
| | - Chenggang Gao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Shihong Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Qingke Duan
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Chunyou Wang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Qiang Shen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Tao Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
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17
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Eberle-Singh JA, Sagalovskiy I, Maurer HC, Sastra SA, Palermo CF, Decker AR, Kim MJ, Sheedy J, Mollin A, Cao L, Hu J, Branstrom A, Weetall M, Olive KP. Effective Delivery of a Microtubule Polymerization Inhibitor Synergizes with Standard Regimens in Models of Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2019; 25:5548-5560. [PMID: 31175095 DOI: 10.1158/1078-0432.ccr-18-3281] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 03/26/2019] [Accepted: 06/03/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that is broadly chemoresistant, due in part to biophysical properties of tumor stroma, which serves as a barrier to drug delivery for most classical chemotherapeutic drugs. The goal of this work is to evaluate the preclinical efficacy and mechanisms of PTC596, a novel agent with potent anticancer properties in vitro and desirable pharmacologic properties in vivo.Experimental Design: We assessed the pharmacology, mechanism, and preclinical efficacy of PTC596 in combination with standards of care, using multiple preclinical models of PDA. RESULTS We found that PTC596 has pharmacologic properties that overcome the barrier to drug delivery in PDA, including a long circulating half-life, lack of P-glycoprotein substrate activity, and high systemic tolerability. We also found that PTC596 combined synergistically with standard clinical regimens to improve efficacy in multiple model systems, including the chemoresistant genetically engineered "KPC" model of PDA. Through mechanistic studies, we learned that PTC596 functions as a direct microtubule polymerization inhibitor, yet a prior clinical trial found that it lacks peripheral neurotoxicity, in contrast to other such agents. Strikingly, we found that PTC596 synergized with the standard clinical backbone regimen gemcitabine/nab-paclitaxel, yielding potent, durable regressions in a PDX model. Moreover, similar efficacy was achieved in combination with nab-paclitaxel alone, highlighting a specific synergistic interaction between two different microtubule-targeted agents in the setting of pancreatic ductal adenocarcinoma. CONCLUSIONS These data demonstrate clear rationale for the development of PTC596 in combination with standard-of-care chemotherapy for PDA.
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Affiliation(s)
- Jaime A Eberle-Singh
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Irina Sagalovskiy
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - H Carlo Maurer
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Stephen A Sastra
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Carmine F Palermo
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | - Amanda R Decker
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
| | | | | | - Anna Mollin
- PTC Therapeutics, South Plainfield, New Jersey
| | | | - Jianhua Hu
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.,Department of Biostatistics, Columbia University Medical Center, New York, New York
| | | | | | - Kenneth P Olive
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York. .,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York
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18
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Liu Y, Zhu D, Xing H, Hou Y, Sun Y. A 6‑gene risk score system constructed for predicting the clinical prognosis of pancreatic adenocarcinoma patients. Oncol Rep 2019; 41:1521-1530. [PMID: 30747226 PMCID: PMC6365694 DOI: 10.3892/or.2019.6979] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 12/06/2018] [Indexed: 12/24/2022] Open
Abstract
Pancreatic adenocarcinoma (PAC) is the most common type of pancreatic cancer, which commonly has an unfavorable prognosis. The present study aimed to develop a novel prognostic prediction strategy for PAC patients. mRNA sequencing data of PAC (the training dataset) were extracted from The Cancer Genome Atlas database, and the validation datasets (GSE62452 and GSE79668) were acquired from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between good and poor prognosis groups were analyzed by limma package, and then prognosis‑associated genes were screened using Cox regression analysis. Subsequently, the risk score system was constructed and confirmed using Kaplan‑Meier (KM) survival analysis. After the survival associated‑clinical factors were screened using Cox regression analysis, they were performed with stratified analysis. Using DAVID tool, the DEGs correlated with risk scores were conducted with enrichment analysis. The results revealed that there were a total of 242 DEGs between the poor and good prognosis groups. Afterwards, a risk score system was constructed based on 6 prognosis‑associated genes (CXCL11, FSTL4, SEZ6L, SPRR1B, SSTR2 and TINAG), which was confirmed in both the training and validation datasets. Cox regression analysis showed that risk score, targeted molecular therapy, and new tumor (the new tumor event days after the initial treatment according to the TCGA database) were significantly related to clinical prognosis. Under the same clinical condition, 6 clinical factors (age, history of chronic pancreatitis, alcohol consumption, radiation therapy, targeted molecular therapy and new tumor (event days) had significant associations with clinical prognosis. Under the same risk condition, only targeted molecular therapy was significantly correlated with clinical prognosis. In conclusion, the 6‑gene risk score system may be a promising strategy for predicting the outcome of PAC patients.
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Affiliation(s)
- Yan Liu
- Department of Anesthesiology, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Dongyan Zhu
- Department of Vascular Surgery, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Hongjian Xing
- Department of Orthopedics, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yi Hou
- Department of Urology, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yan Sun
- Department of Anesthesiology, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
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Wang X, Wu K, Xiao LK, Wu XY. ShRNA-mediated BMI-1 gene silencing inhibits gastrointestinal stromal tumor cell telomerase activity and enhances apoptosis. Kaohsiung J Med Sci 2018; 34:606-615. [PMID: 30392567 DOI: 10.1016/j.kjms.2018.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 11/15/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most frequently occurring mesenchymal tumors of the gastrointestinal tract. Telomerase activity is well acknowledged as a critical factor in oncogenesis. The objective of the present study is to evaluate the effect of BMI gene silencing on proliferation, apoptosis and telomerase activity in human GIST882 cells. GIST882 cells were transfected with a eukaryotic expression vector of an shRNA fragment. The silencing efficiency in the GIST882 cells was determined by RT-qPCR and a western blot analysis. After the shRNA-BMI-1 plasmid was transfected into the GIST882 cells and nude mice, a cell counting kit-8 (CCK-8) assay and flow cytometry were utilized to detect the GIST882 cell proliferation, the apoptosis rate and the cell cycle. Tumor growth was observed by tumor xenograft in nude mice. Telomerase activity and telomere length were detected by a Southern blot and a target region amplified polymorphism. The shRNA-BMI-1 recombinant plasmid was successfully constructed. The mRNA and protein expression of the BMI-1 gene in GIST882 cells was suppressed by the shRNA-BMI-1 recombinant plasmid. Meanwhile, BMI-1 gene silencing inhibited the cell proliferation, tumor growth, and cell cycle in the GIST882 cells. However, cell apoptosis was increased and telomerase activity was decreased with the silencing of the BMI-1 gene. Collectively, the results of this study suggest that silencing the BMI-1 gene may provide a new target for the treatment of GISTs.
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Affiliation(s)
- Xin Wang
- Department of General Surgery, Chongqing General Hospital (Zhongshan Branch), Chongqing, PR China.
| | - Kun Wu
- Department of General Surgery, Chongqing General Hospital (Zhongshan Branch), Chongqing, PR China
| | - Lin-Kang Xiao
- Department of General Surgery, Chongqing General Hospital (Zhongshan Branch), Chongqing, PR China
| | - Xing-Ye Wu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
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20
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Xin T, Zhang FB, Sui GJ, Jin XM. Bmi-1 siRNA inhibited ovarian cancer cell line growth and decreased telomerase activity. Br J Biomed Sci 2018. [DOI: 10.1080/09674845.2012.12002438] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- T. Xin
- Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - F. B. Zhang
- Affiliated Oncology Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - G. J. Sui
- Affiliated Oncology Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - X. M. Jin
- Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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21
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Kowolik CM, Lin M, Xie J, Overman LE, Horne DA. NT1721, a novel epidithiodiketopiperazine, exhibits potent in vitro and in vivo efficacy against acute myeloid leukemia. Oncotarget 2018; 7:86186-86197. [PMID: 27863389 PMCID: PMC5349906 DOI: 10.18632/oncotarget.13364] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 11/07/2016] [Indexed: 12/24/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected. The IC50 values for NT1721 were significantly lower than those for clinically used AML drugs (i.e. cytarabine, sorafenib) in all tested AML cell lines regardless of their FLT3 mutation status. Moreover, combinations of NT1721 with sorafenib or cytarabine showed better antileukemic effects than the single agents in vitro. Combining cytarabine with NT1721 also attenuated the cytarabine-induced FLT3 ligand surge that has been linked to resistance to tyrosine kinase inhibitors. Mechanistically, NT1721 depleted DNA methyltransferase 1 (DNMT1) protein levels, leading to the re-expression of silenced tumor suppressor genes and apoptosis induction. NT1721 concomitantly decreased the expression of EZH2 and BMI1, two genes that are associated with the maintenance of leukemic stem/progenitor cells. In a systemic FLT3-ITD+ AML mouse model, treatment with NT1721 reduced tumor burdens by > 95% compared to the control and significantly increased survival times. Taken together, our results suggest that NT1721 may represent a promising novel agent for the treatment of AML.
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Affiliation(s)
- Claudia M Kowolik
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Min Lin
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jun Xie
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Larry E Overman
- Department of Chemistry, University of California, Irvine, CA 92697, USA
| | - David A Horne
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
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22
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Liu J, Liu K, Jiang X, Wang X, Chen Y, Cui X, Pang L, Li S, Liu C, Zou H, Yang L, Zhao J, Qi Y, Hu JM, Li F. Clinicopathological significance of Bmi-1 overexpression in esophageal cancer: a meta-analysis. Biomark Med 2017; 12:71-81. [PMID: 29240461 DOI: 10.2217/bmm-2017-0092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
AIM The clinicopathological effects of Bmi-1 expression in esophageal cancer remain widely disputed. Our aim was to clarify this relationship. METHODS Available studies were retrieved from diverse databases. Review Manager 5.3 and Stata 12.0 software were used to identify correlations between Bmi-1 expression and the clinicopathological features of esophageal cancer. RESULTS From 16 studies, 1523 esophageal cancer patients were analyzed. Meta-analysis demonstrated that Bmi-1 overexpression was associated with differentiation (p = 0.03), tumor/node/metastasis stage (p = 0.02), depth of invasion (p = 0.0006) and lymph node metastasis (p = 0.008). CONCLUSION The expression of Bmi-1 is associated with the progression and invasion of esophageal cancer.
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Affiliation(s)
- Jihong Liu
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Kai Liu
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Xianli Jiang
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Xueli Wang
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Yunzhao Chen
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Xiaobin Cui
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Lijuan Pang
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Shugang Li
- Department of Preventive Medicine, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Chunxia Liu
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Hong Zou
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Lan Yang
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Jin Zhao
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Yan Qi
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Jian Ming Hu
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China
| | - Feng Li
- Department of Pathology & Key Laboratory for Xinjiang Endemic & Ethnic Diseases, Shihezi University School of Medicine, Xinjiang 832002, PR China.,Department of Pathology, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, PR China
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23
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Li H, Wu Y, Li P. MicroRNA-452 suppresses pancreatic cancer migration and invasion by directly targeting B-cell-specific Moloney murine leukemia virus insertion site 1. Oncol Lett 2017; 14:3235-3242. [PMID: 28927071 DOI: 10.3892/ol.2017.6566] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 04/28/2017] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer, one of the most common cancers globally, is the fourth most common cause of cancer-associated mortality in the USA. The 5-year relative survival rate for patients with pancreatic cancer is ~5% and the median survival time is only 6 months. The poor prognosis is mainly due to early and aggressive local invasion and metastasis, as well as dissemination of the pancreatic cancer cells. The present study demonstrated that microRNA-452 (miR-452) was markedly downregulated in pancreatic cancer tissues, particularly in metastatic tumors and pancreatic cancer cell lines. Overexpression of miR-452 significantly inhibited migration and invasion in pancreatic cancer cells. In addition, the molecular mechanism underlying the inhibitory functions of miR-452 in pancreatic cancer was also investigated. The results indicated that B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) was a direct target gene of miR-452 in pancreatic cancer. Overexpression of miR-452 inhibited the migration and invasion of pancreatic cancer, at least partially by knockdown of BMI1 expression. The results provided novel insight with potential therapeutic applications for the treatment of metastatic pancreatic cancer.
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Affiliation(s)
- Hongyan Li
- Department of Endocrinology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Yan Wu
- Department of Endocrinology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Peixiu Li
- Department of Endocrinology, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
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24
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Wang MC, Jiao M, Wu T, Jing L, Cui J, Guo H, Tian T, Ruan ZP, Wei YC, Jiang LL, Sun HF, Huang LX, Nan KJ, Li CL. Polycomb complex protein BMI-1 promotes invasion and metastasis of pancreatic cancer stem cells by activating PI3K/AKT signaling, an ex vivo, in vitro, and in vivo study. Oncotarget 2017; 7:9586-99. [PMID: 26840020 PMCID: PMC4891062 DOI: 10.18632/oncotarget.7078] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Accepted: 01/02/2016] [Indexed: 12/27/2022] Open
Abstract
Cancer stem cell theory indicates cancer stem cells are the key to promote tumor invasion and metastasis. Studies showed that BMI-1 could promote self-renew, differentiation and tumor formation of CSCs and invasion/metastasis of human cancer. However, whether BMI-1 could regulate invasion and metastasis ability of CSCs is still unclear. In our study, we found that up-regulated expression of BMI-1 was associated with tumor invasion, metastasis and poor survival of pancreatic cancer patients. CD133+ cells were obtained by using magnetic cell sorting and identified of CSCs properties such as self-renew, multi-differentiation and tumor formation ability. Then, we found that BMI-1 expression was up-regulated in pancreatic cancer stem cells. Knockdown of BMI-1 expression attenuated invasion ability of pancreatic cancer stem cells in Transwell system and liver metastasis capacity in nude mice which were injected CSCs through the caudal vein. We are the first to reveal that BMI-1 could promote invasion and metastasis ability of pancreatic cancer stem cells. Finally, we identified that BMI-1 expression activating PI3K/AKT singing pathway by negative regulating PTEN was the main mechanism of promoting invasion and metastasis ability of pancreatic CSCs. In summary, our findings indicate that BMI-1 could be used as the therapeutic target to inhibiting CSCs-mediated pancreatic cancer metastasis.
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Affiliation(s)
- Min-Cong Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Min Jiao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Tao Wu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Li Jing
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Jie Cui
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Hui Guo
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Tao Tian
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Zhi-ping Ruan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Yong-Chang Wei
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Li-Li Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Hai-Feng Sun
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Lan-Xuan Huang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Ke-Jun Nan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Chun-Li Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
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25
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Zhai R, Tang F, Gong J, Zhang J, Lei B, Li B, Wei Y, Liang X, Tang B, He S. The relationship between the expression of USP22, BMI1, and EZH2 in hepatocellular carcinoma and their impacts on prognosis. Onco Targets Ther 2016; 9:6987-6998. [PMID: 27920552 PMCID: PMC5125798 DOI: 10.2147/ott.s110985] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Recent studies have shown that deubiquitination plays a key role in tumor progression, metastasis, resistance to chemotherapy drugs, and prognosis. In this study, we investigated the effects of the deubiquitinating enzyme USP22 on the expression of the drug-resistance genes BMI1 and EZH2 in hepatocellular carcinoma (HCC) and on prognosis. Downregulation of USP22 expression with interference ribonucleic acid in resistant HCC cell lines with high USP22 expression resulted in decreased BMI1 expression, but had no effect on EZH2 expression. USP22, BMI1, and EZH2 were highly expressed in HCC tissue, and the expression levels were positively correlated with tumor grade and clinical stage. Correlation analysis showed that USP22 expression was positively correlated with that of BMI1. Kaplan–Meier analysis showed that high levels of USP22 and BMI1 expression were associated with poor overall survival and relapse-free survival in all of the cases and in patients treated with transcatheter arterial chemoembolization. These results suggested that high levels of USP22 expression played an important role in drug resistance to chemotherapeutic drugs in HCC patients by upregulating the expression of BMI1; therefore, coexpression of USP22 and BMI1 may become a new predictor for HCC prognosis and may help guide clinical treatment.
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Affiliation(s)
- Run Zhai
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Fang Tang
- Pathology Department, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Jianhua Gong
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Jing Zhang
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Biao Lei
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Bo Li
- Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Yangchao Wei
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Xingsi Liang
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Bo Tang
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Songqing He
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, Guangxi, People's Republic of China
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26
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Wu SQ, Niu WY, Li YP, Huang HB, Zhan R. miR-203 inhibits cell growth and regulates G1/S transition by targeting Bmi-1 in myeloma cells. Mol Med Rep 2016; 14:4795-4801. [PMID: 27748826 DOI: 10.3892/mmr.2016.5832] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 08/30/2016] [Indexed: 11/06/2022] Open
Abstract
The oncogene B-cell-specific Moloney murine leukemia virus insertion site‑1 (Bmi‑1) is overexpressed in multiple myeloma (MM). Our previous study demonstrated that Bmi‑1 silencing sensitized MM cells to bortezomib. Translational regulation has emerged as a prominent underlying mechanism of Bmi‑1 regulation, particularly via microRNA targeting. The present study determined that Bmi‑1 may be directly targeted by miR‑203 using a luciferase assay. In addition, enforced expression of miR-203 led to significant downregulation of Bmi‑1 protein and mRNA expression levels. Furthermore, restoration of miR-203 significantly inhibited cell growth and G1/S transition in MM cells. miR‑203 was downregulated in MM patients, and a negative correlation between the expression of miR‑203 and Bmi‑1 was observed. The results of the present study indicated that miR‑203 exerts growth‑inhibiting effects in MM through the suppression of Bmi‑1 expression. In conclusion, the present study demonstrated that Bmi‑1 is a direct functional target of miR-203 in MM.
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Affiliation(s)
- Shun-Quan Wu
- Department of Hematology, Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Wen-Yan Niu
- Department of Hematology, Tengzhou Central People's Hospital, Tengzhou, Shandong 277500, P.R. China
| | - Ya-Ping Li
- Department of Hematology, Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Hao-Bo Huang
- Department of Hematology, Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Rong Zhan
- Department of Hematology, Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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27
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Wang X, Wang C, Zhang X, Hua R, Gan L, Huang M, Zhao L, Ni S, Guo W. Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. J Hematol Oncol 2016; 9:90. [PMID: 27644439 PMCID: PMC5029045 DOI: 10.1186/s13045-016-0323-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 09/09/2016] [Indexed: 12/18/2022] Open
Abstract
Background B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) plays an important role in regulating stemness in some kinds of cancer. However, the mechanisms remain unclear. This study was to investigate whether and how Bmi-1 regulates stemness of gastric cancer. Methods We firstly explored the role of Bmi-1 in regulating stem cell-like features in gastric cancer. Secondly, we screened out its downstream miRNAs and clarified whether these miRNAs are involved in the regulation of stemness. Finally, we investigated the mechanisms how Bmi-1 regulates miRNAs. Results Bmi-1 positively regulates stem cell-like properties of gastric cancer and upregulates miR-21 and miR-34a. There was a positive correlation between Bmi-1 and miR-21 expression in gastric cancer tissues. MiR-21 mediated the function of Bmi-1 in regulating stem cell-like properties, while miR-34a negatively regulates stem cell-like characteristics via downregulating Bmi-1. Bmi-1 binds to PTEN promoter and directly inhibits PTEN and thereafter activates AKT. Bmi-1 also regulates p53 and PTEN via miR-21. Bmi-1 activated NF-kB via AKT and enhanced the binding of NF-kB to the promoter of miR-21 and miR-34a and increased their expression. Conclusions Bmi-1 positively regulates stem cell-like properties via upregulating miR-21, and miR-34a negatively regulates stem cell-like characteristics by negative feedback regulation of Bmi-1 in gastric cancer. Bmi-1 upregulates miR-21 and miR-34a by activating AKT-NF-kB pathway. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0323-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaofeng Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chang Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruixi Hua
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lu Gan
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Mingzhu Huang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Liqin Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Sujie Ni
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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28
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You N, Li J, Gong Z, Huang X, Wang W, Wang L, Wu K, Zheng L. COMMD7 functions as molecular target in pancreatic ductal adenocarcinoma. Mol Carcinog 2016; 56:607-624. [PMID: 27350032 DOI: 10.1002/mc.22520] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 04/28/2016] [Accepted: 06/26/2016] [Indexed: 02/04/2023]
Abstract
Our previous studies provided evidence that COMMD7 was associated with tumor progression in human solid cancer. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in pancreatic ductal adenocarcinoma (PDAC). We found that high COMMD7 expression was specifically detected in PDAC tissues and PDAC cell lines. In addition, COMMD7 overexpression positively correlated with histological differentiation and tumor node metastasis (TNM) stage. Patients with high COMMD7 expression had significantly poorer overall survival, and high COMMD7 expression was an independent predictor of poor prognosis. To further explore the regulatory mechanism of COMMD7, we used stable short hairpin RNA (shRNA)-mediated knockdown and divided the work into in vitro and in vivo experiments. In vitro, the anti-proliferation effects of COMMD7 inhibition were observed under long-time stress conditions, which correlated with cyclin D1 and Bcl-2 downregulation and Bax upregulation. We found that under short-time stress conditions, decreased COMMD7 expression also inhibited PDAC cell invasion in vitro which decreased the secretion of matrix metalloproteinase 2 (MMP-2). Moreover, extracellular signal-regulated kinase1/2 (ERK1/2) was identified as a direct target of COMMD7. The inhibition of ERK1/2 activity under short- or long-time stress conditions using specific inhibitors in COMMD7 inhibition cells all exhibited a strong tumorigenic role. In vivo, COMMD7 was sufficient to impair tumor growth. Our results suggest that COMMD7 plays an important role in the late progression of PDAC and is a potential novel target. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nan You
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Jing Li
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Zhenbin Gong
- Center of Hepatobiliary Surgery of Lanzhou Army Region, Lanzhou, P. R. China
| | - Xiaobing Huang
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Weiwei Wang
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Liang Wang
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Ke Wu
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
| | - Lu Zheng
- Department of Hepatobiliary Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, P. R. China
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Deng Y, Xiong Y, Liu Y. miR-376c inhibits cervical cancer cell proliferation and invasion by targeting BMI1. Int J Exp Pathol 2016; 97:257-65. [PMID: 27345009 DOI: 10.1111/iep.12177] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 01/31/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) play crucial roles in cancer development and progression. The purposes of this study were to explore the role of miR-376c in cervical cancer and to clarify the regulation of BMI1 by miR-376c. Quantitative RT-PCR was used to measure miR-376c expression in cervical cancer tissues and cell lines. The cell proliferation, cell cycle and Transwell invasion assays were performed. A luciferase reporter assay was conducted to confirm the target gene of miR-376c, and the results were validated in cervical cancer cell lines and tissues. MiR-376c was significantly downregulated in cervical cancer cell lines and clinical tissues. Upregulation of miR-376c impaired cell proliferation, blocked G1/S checkpoint of cell cycle and suppressed cell invasion in vitro. BMI1 was verified as a direct target of miR-376c, which was further confirmed by the inverse expression of miR-376c and BMI1 in patient specimens. The newly identified miR-376c/BMI1 pathway provides an insight into cervical cancer progression and may represent a novel therapeutic target.
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Affiliation(s)
- Youping Deng
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yan Xiong
- Department of gynaecology oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yingjuan Liu
- Medical Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
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30
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Yang XX, Sang MX, Zhu SC, Liu ZK, Ma M. Radiosensitization of esophageal carcinoma cells by the silencing of BMI-1. Oncol Rep 2016; 35:3669-78. [PMID: 27108688 DOI: 10.3892/or.2016.4744] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 01/08/2016] [Indexed: 11/05/2022] Open
Abstract
Radiotherapy (RT) has been widely used to treat cancer patients, particularly esophageal cancer patients. B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) plays an important role in promoting the growth of cancer cells after exposure to irradiation. The present study aimed to characterize the effects of BMI-1 on the proliferation and invasion of cancer cells, as well as the mechanism involved in the regulation of the growth of esophageal cancer ECA109 and TE13 cells. The expression levels of the BMI-1 gene and protein in esophageal cancer ECA109 and TE13 cells were determined by quantitative PCR and western blotting after transfection. Co-immunoprecipitation (Co-IP) assay was employed to detect the interaction of BMI-1 with r-H2AX and H2AK119ub. We used flow cytometry to analyze the cell cycle distribution and apoptosis of transfected cells after irradiation or not, and examined cellular growth and invasion in vitro by MTS and Transwell assays. The results revealed that shRNA targeting the BMI-1 gene and protein downregulated BMI-1 expression after transfection for 24 h. The proliferation and invasion of tumor cells in the BMI-1‑shRNA group were suppressed after RT. In addition, the interaction of BMI-1, H2AK119ub and r-H2AX was increased after exposure to IR, followed by an increased apoptosis rate and decreased percentage of cells arrested at the G2/M phase after irradiation and silencing of BMI-1 by shRNA. Knockdown of BMI-1 expression decreased the phosphorylation of H2AX, upregulated p16, and induced the radiosensitivity of esophageal cancer ECA109 and TE13 cells in vitro and significantly inhibited the growth and invasion of tumor cells. The mechanisms were found to be abrogation of cell cycle arrest at the G2/M stage and promotion of apoptosis.
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Affiliation(s)
- Xing-Xiao Yang
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Mei-Xiang Sang
- Research Centre, Department of Biotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Shu-Chai Zhu
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhi-Kun Liu
- Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Ming Ma
- Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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31
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Chen SJ, Chen YT, Zeng LJ, Zhang QB, Lian GD, Li JJ, Yang KG, Huang CM, Li YQ, Chu ZH, Huang KH. Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro. Tumour Biol 2016; 37:11299-309. [PMID: 26951514 DOI: 10.1007/s13277-016-4840-5] [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] [Received: 10/29/2015] [Accepted: 01/11/2016] [Indexed: 12/30/2022] Open
Abstract
It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.
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Affiliation(s)
- Shao-Jie Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yin-Ting Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lin-Juan Zeng
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China
| | - Qiu-Bo Zhang
- Department of Gastroenterology, Lihuili Hospital of Ningbo Medical Center, Ningbo, China
| | - Guo-da Lian
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jia-Jia Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ke-Ge Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chu-Mei Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ya-Qing Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhong-Hua Chu
- Department of Gastroenteropancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.
| | - Kai-Hong Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China. .,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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32
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Wang MC, Li CL, Cui J, Jiao M, Wu T, Jing LI, Nan KJ. BMI-1, a promising therapeutic target for human cancer. Oncol Lett 2015; 10:583-588. [PMID: 26622537 DOI: 10.3892/ol.2015.3361] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 03/12/2015] [Indexed: 12/31/2022] Open
Abstract
BMI-1 oncogene is a member of the polycomb-group gene family and a transcriptional repressor. Overexpression of BMI-1 has been identified in various human cancer tissues and is known to be involved in cancer cell proliferation, cell invasion, distant metastasis, chemosensitivity and patient survival. Accumulating evidence has revealed that BMI-1 is also involved in the regulation of self-renewal, differentiation and tumor initiation of cancer stem cells (CSCs). However, the molecular mechanisms underlying these biological processes remain unclear. The present review summarized the function of BMI-1 in different human cancer types and CSCs, and discussed the signaling pathways in which BMI-1 is potentially involved. In conclusion, BMI-1 may represent a promising target for the prevention and therapy of various cancer types.
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Affiliation(s)
- Min-Cong Wang
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Chun-Li Li
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jie Cui
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Min Jiao
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Tao Wu
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - L I Jing
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Ke-Jun Nan
- Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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33
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Context-dependent actions of Polycomb repressors in cancer. Oncogene 2015; 35:1341-52. [DOI: 10.1038/onc.2015.195] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 04/15/2015] [Accepted: 05/05/2015] [Indexed: 12/21/2022]
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34
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Bednar F, Schofield HK, Collins MA, Yan W, Zhang Y, Shyam N, Eberle JA, Almada LL, Olive KP, Bardeesy N, Fernandez-Zapico ME, Nakada D, Simeone DM, Morrison SJ, Pasca di Magliano M. Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. Carcinogenesis 2015; 36:730-8. [PMID: 25939753 DOI: 10.1093/carcin/bgv058] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 04/25/2015] [Indexed: 12/13/2022] Open
Abstract
Epigenetic dysregulation is involved in the initiation and progression of many epithelial cancers. BMI1, a component of the polycomb protein family, plays a key role in these processes by controlling the histone ubiquitination and long-term repression of multiple genomic loci. BMI1 has previously been implicated in pancreatic homeostasis and the function of pancreatic cancer stem cells. However, no work has yet addressed its role in the early stages of pancreatic cancer development. Here, we show that BMI1 is required for the initiation of murine pancreatic neoplasia using a novel conditional knockout of Bmi1 in combination with a Kras(G12D)-driven pancreatic cancer mouse model. We also demonstrate that the requirement for Bmi1 in pancreatic carcinogenesis is independent of the Ink4a/Arf locus and at least partially mediated by dysregulation of reactive oxygen species. Our data provide new evidence of the importance of this epigenetic regulator in the genesis of pancreatic cancer.
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Affiliation(s)
| | | | | | - Wei Yan
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA, Present address: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
| | | | | | - Jaime A Eberle
- Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Luciana L Almada
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Kenneth P Olive
- Departments of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Nabeel Bardeesy
- Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Martin E Fernandez-Zapico
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Daisuke Nakada
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Diane M Simeone
- Department of Surgery, Department of Molecular and Integrative Physiology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sean J Morrison
- Children's Research Institute, Department of Pediatrics, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA and
| | - Marina Pasca di Magliano
- Department of Surgery, Program in Cell and Molecular Biology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA and
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35
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Wang M, Zhang CJ, Xu F, Zhao LQ. Clinical significance of expression of Bmi-1 and Mina53 in colorectal carcinoma. Shijie Huaren Xiaohua Zazhi 2015; 23:1420-1425. [DOI: 10.11569/wcjd.v23.i9.1420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the clinicopathological significance of expression of B-cell-specific moloney murine leukemia virus insertion site 1 (Bmi-1) and myc-induced nuclear antigen with a molecular mass of 53 kDa (Mina53) in colorectal carcinoma.
METHODS: The expression of Bmi-1 and Mina53 proteins was detected by immunohistochemistry in 56 colorectal cancer samples and matched tumor-adjacent normal tissue samples. The correlation between the expression of these proteins and the clinicopathologic features of colorectal carcinoma was analyzed.
RESULTS: The positive rates of Bmi-1 expression and Mina53 in colorectal cancer were significantly higher than those in matched tumor-adjacent normal tissue (80.4% vs 35.7%, 73.2% vs 19.6%, χ2 = 22.913, 32.308, P < 0.05 for both). Expression of Bmi-1 and Mina53 was significantly associated with tumor differentiation, lymph node metastasis and tumor infiltration depth in colorectal carcinoma (P < 0.05 for all), but not with age or gender (P > 0.05 for both). A positive correlation was noted between the expression of Bmi-1 and that of Mina53 in colorectal carcinoma (r = 0.296, P < 0.05).
CONCLUSION: High expression of Bmi-1 and Mina53 proteins may participate in the occurrence, progression and prognosis of colorectal carcinoma. Combined detection of the expression of these proteins is helpful to the diagnosis and evaluation of the prognosis of colorectal carcinoma.
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36
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Shao Y, Geng Y, Gu W, Ning Z, Jiang J, Pei H. Prognostic role of high Bmi-1 expression in Asian and Caucasian patients with solid tumors: a meta-analysis. Biomed Pharmacother 2014; 68:969-77. [PMID: 25458792 DOI: 10.1016/j.biopha.2014.10.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 10/15/2014] [Indexed: 12/14/2022] Open
Abstract
Recently, many studies have shown that the B-cell-specific moloney leukemia virus insertion site 1 (Bmi-1) exhibits altered expression in various cancers and may serve as prognostic biomarkers. We performed a meta-analysis to evaluate the prognostic role of Bmi-1 expression in solid cancers. Studies were recruited by searching PubMed, Embase and the Cochrane Library. Thirty-nine articles including 40 studies were involved in this meta-analysis. Our results indicated that the Bmi-1 showed the opposite prognostic effect in Asian and Caucasian populations. High Bmi-1 expression as a negative predictor for overall survival (OS) in Asian patients (HR=1.96, 95% CI 1.62-2.36), but a positive predictor in Caucasian populations (HR=0.77, 95% CI 0.63-0.93). Furthermore, we took a further subgroup analysis based on tumor type in these two populations, respectively. In Asian cases, high expression of Bmi-1 was associated with poor OS in oesophageal carcinoma (HR=1.93, 95% CI 1.52-2.46), gastric cancer (HR=1.50, 95% CI 1.22-1.85), lung cancer (HR=1.73, 95% CI 1.05-2.85), cervical cancer (HR=2.80, 95% CI 2.26-3.47) and colorectal cancer (HR=3.36, 95% CI 2.19-5.15), rather than in breast cancer and HCC. In Caucasian populations, high expression of Bmi-1 was associated with better OS in breast cancer (HR=0.70, 95% CI 0.51-0.97), but it showed no significance in oesophageal carcinoma. In conclusion, high Bmi-1 expression was significantly associated with poor survival in Asian patients with oesophageal carcinoma, gastric cancer, lung cancer, colorectal cancer and cervical carcinoma, whereas high level of Bmi-1 can predict better prognosis in Caucasian patients with breast cancer.
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Affiliation(s)
- Yingjie Shao
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, PR China
| | - Yiting Geng
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, PR China
| | - Wendong Gu
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, PR China
| | - Zhonghua Ning
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, PR China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, PR China.
| | - Honglei Pei
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, PR China.
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37
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Qi X, Li J, Zhou C, Lv C, Tian M. MicroRNA-320a inhibits cell proliferation, migration and invasion by targeting BMI-1 in nasopharyngeal carcinoma. FEBS Lett 2014; 588:3732-8. [PMID: 25171860 DOI: 10.1016/j.febslet.2014.08.021] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 08/18/2014] [Accepted: 08/18/2014] [Indexed: 12/12/2022]
Abstract
In the present study, we investigated the roles and molecular mechanisms of miR-320a in human nasopharyngeal carcinoma (NPC). miR-320a expression was strongly reduced in NPC tissues and cell lines. Overexpression of miR-320a significantly suppressed NPC cell growth, migration, invasion and tumor growth in a xenograft mouse model. A luciferase reporter assay revealed that miR-320a could directly bind to the 3' UTR of BMI-1. Overexpression of BMI-1 rescued miR-320a-mediated biological function. BMI-1 expression was found to be up-regulated and inversely correlated with miR-320a expression in NPC. Collectively, our data indicate that miR-320a plays a tumor suppressor role in the development and progression of NPC and may be a novel therapeutic target against NPC.
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Affiliation(s)
- Xiaoming Qi
- Department of E.N.T., The 88th Hospital of PLA, Tai'an, Shandong 271000, China
| | - Jianqiang Li
- Department of E.N.T., The 88th Hospital of PLA, Tai'an, Shandong 271000, China
| | - Changbo Zhou
- Department of E.N.T., The 88th Hospital of PLA, Tai'an, Shandong 271000, China
| | - Chunlei Lv
- Department of E.N.T., The 88th Hospital of PLA, Tai'an, Shandong 271000, China
| | - Min Tian
- Department of Orthopedics, The 88th Hospital of PLA, Tai'an, Shandong 271000, China.
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38
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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: 64] [Impact Index Per Article: 5.8] [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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39
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Zhou L, Zhang WG, Wang DS, Tao KS, Song WJ, Dou KF. MicroRNA-183 is involved in cell proliferation, survival and poor prognosis in pancreatic ductal adenocarcinoma by regulating Bmi-1. Oncol Rep 2014; 32:1734-40. [PMID: 25109303 DOI: 10.3892/or.2014.3374] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 07/03/2014] [Indexed: 11/05/2022] Open
Abstract
As a highly aggressive malignant disease, the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Yet, the mechanisms underlying the progression of PDAC remain unclear. MicroRNAs (miRNAs) may be involved in various human cancers as cancer suppressors or oncogenes. MicroRNA-183 (miR-183) was recently reported to be dysregulated in various types of cancer and to play an important role in the processes of cancer. However, the effects and potential mechanisms of action of miR-183 in PDAC have not been explored. In the present study, low expression of miR-183 was observed in PDAC tissues and cell lines. Low expression of miR-183 in PDAC was significantly associated with tumor grade, metastasis and TNM stage. Kaplan-Meier survival analysis demonstrated that patients harboring low expression of miR-183 had a significantly reduced overall survival than patients with a high level of miR-183 expression. The present study revealed that B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) expression was inversely correlated with miR-183. Our findings also demonstrated that a low level of miR-183 expression effectively suppressed the growth of PDAC cells via regulation of Bmi-1. Following Bmi-1 silencing or upregulation of miR-183, the expression levels of cyclin D1, cyclin-dependent kinase (CDK)2 and CDK4 were decreased. It is reasonable to conclude that alteration of miR-183 expression may regulate the function of PDAC cells by the downregulation of Bmi-1 expression.
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Affiliation(s)
- Liang Zhou
- Department of General Surgery, The 155 Central Hospital of PLA, Kaifeng, Henan 471000, P.R. China
| | - Wei-Guo Zhang
- Department of General Surgery, The 155 Central Hospital of PLA, Kaifeng, Henan 471000, P.R. China
| | - De-Sheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China
| | - Kai-Shan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China
| | - Wen-Jie Song
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China
| | - Ke-Feng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China
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40
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Kuroki H, Hayashi H, Okabe H, Hashimoto D, Takamori H, Nakahara O, Nakagawa S, Fukushima Y, Chikamoto A, Beppu T, Hirota M, Iyama KI, Baba H. EZH2 is associated with malignant behavior in pancreatic IPMN via p27Kip1 downregulation. PLoS One 2014; 9:e100904. [PMID: 25084021 DOI: 10.1371/journal.pone.0100904] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 05/28/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The epigenetic mechanism of tumorigenesis in pancreatic intraductal papillary mucinous neoplasm (IPMN) remains largely unknown. The aim of this study is to examine the role of enhancer of zeste homologue 2 (EZH2) alteration in pancreatic IPMN progression. METHODS Fifty-four surgically resected pancreatic IPMN specimens, including a total of 181 lesions (normal duct in 48, adenoma in 50, borderline atypia in 53, carcinoma in situ (CIS) in 19, and invasive carcinoma in 11) were analyzed by immunohistochemical staining (EZH2, Ki-67, p27Kip1). Using paraffin embedded sections, total RNA was successfully extracted from 20 IPMN lesions (borderline IPMN in 9, CIS in 6, invasive carcinoma in 5) and 7 pancreatic normal ducts, and then levels of EZH2 and p27Kip1 mRNA were analyzed by real time PCR. RESULTS In immunohistochemical analysis, cell proliferative activity revealed by Ki-67 positive nuclei was increased during IPMN progression (normal duct<adenoma<borderline atypia<CIS ≈ invasive carcinoma). EZH2 expression displayed a similar pattern (normal duct<adenoma<borderline atypia<CIS ≈ invasive carcinoma) with cell proliferative activity. EZH2 expression in malignant (CIS and invasive carcinoma) IPMNs was significantly higher than that in adenoma and borderline-atypia IPMNs. EZH2 expression level in IPMN lesions was positively correlated with the Ki-67 positive nuclear ratio (p<0.0001). EZH2-positive cells in malignant IPMN did not express p27Kip1. EZH2 mRNA expressions in malignant lesions were significantly higher than those in benign lesions (p<0.0001). In contrast, p27Kip1 mRNA in malignant lesions was significantly decreased compared to those in benign lesion (p<0.05), and there was an inverse correlation between EZH2 and p27Kip1 mRNA levels (p = 0.0109). CONCLUSION EZH2 is associated with the accelerated cell proliferation and malignant step in pancreatic IPMN via the downregulation of p27Kip1.
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Affiliation(s)
- Hideyuki Kuroki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hirohisa Okabe
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Daisuke Hashimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroshi Takamori
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Osamu Nakahara
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yukiko Fukushima
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Akira Chikamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Toru Beppu
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masahiko Hirota
- Department of Surgery, Kumamoto Regional Medical Center, Kumamoto, Japan
| | - Ken-ichi Iyama
- Department of Surgical Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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41
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Neureiter D, Jäger T, Ocker M, Kiesslich T. Epigenetics and pancreatic cancer: Pathophysiology and novel treatment aspects. World J Gastroenterol 2014; 20:7830-7848. [PMID: 24976721 PMCID: PMC4069312 DOI: 10.3748/wjg.v20.i24.7830] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/07/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16ink4a, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.
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Dang Z, Xu WH, Lu P, Wu N, Liu J, Ruan B, Zhou L, Song WJ, Dou KF. MicroRNA-135a inhibits cell proliferation by targeting Bmi1 in pancreatic ductal adenocarcinoma. Int J Biol Sci 2014; 10:733-45. [PMID: 25013381 PMCID: PMC4081607 DOI: 10.7150/ijbs.8097] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 05/31/2014] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal solid tumor due to the lack of reliable early detection markers and effective therapies. MicroRNAs (miRNAs), noncoding RNAs that regulate gene expression, are involved in tumorigenesis and have a remarkable potential for the diagnosis and treatment of malignancy. In this study, we investigated aberrantly expressed miRNAs involved in PDAC by comparing miRNA expression profiles in PDAC cell lines with a normal pancreas cell line and found that miR-135a was significantly down-regulated in the PDAC cell lines. The microarray results were validated by qRT-PCR in PDAC tissues, paired adjacent normal pancreatic tissues, PDAC cell lines, and a normal pancreas cell line. We then defined the tumor-suppressing significance and function of miR-135a by constructing a lentiviral vector to express miR-135a. The overexpression of miR-135a in PDAC cells decreased cell proliferation and clonogenicity and also induced G1 arrest and apoptosis. We predicted Bmi1 may be a target of miR-135a using bioinformatics tools and found that Bmi1 expression was markedly up-regulated in PDAC. Its expression was inversely correlated with miR-135a expression in PDAC. Furthermore, a luciferase activity assay revealed that miR-135a could directly target the 3'-untranslated region (3'-UTR) of Bmi1. Taken together, these results demonstrate that miR-135a targets Bmi1 in PDAC and functions as a tumor suppressor. miR-135a may offer a new perspective for the development of effective miRNA-based therapy for PDAC.
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Affiliation(s)
- Zheng Dang
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China ; 2. Department of Hepatobiliary Surgery, Lanzhou General Hospital of PLA, Lanzhou, Gansu 730050, P.R. China
| | - Wei-Hua Xu
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Peng Lu
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China ; 3. Department of General Surgery, The 518 Central Hospital of PLA, Xi'an, Shanxi 710043, P.R. China
| | - Nan Wu
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jie Liu
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Bai Ruan
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Liang Zhou
- 4. Department of General Surgery, The 155 Central Hospital of PLA, Kaifeng, He'nan 471000 P.R. China
| | - Wen-Jie Song
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Ke-Feng Dou
- 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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Pun JCS, Chan JYJ, Chun BKM, Ng KW, Tsui SYK, Wan TMH, Lo O, Poon JTC, Ng L, Pang R. Plasma Bmi1 mRNA as a potential prognostic biomarker for distant metastasis in colorectal cancer patients. Mol Clin Oncol 2014; 2:817-820. [PMID: 25054051 DOI: 10.3892/mco.2014.321] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 04/01/2014] [Indexed: 01/21/2023] Open
Abstract
Bmi1 is overexpressed in gastrointestinal cancers, including colorectal cancer (CRC); however, its role as a non-invasive biomarker in CRC has not been established. The aim of this study was to compare the plasma Bmi1 mRNA levels prior to and following curative resection of the primary tumor in CRC patients and to determine their association with the clinicopathological parameters. The plasma Bmi1 mRNA level was measured by quantitative polymerase chain reaction and expressed as cycle threshold value. There was no significant difference between the overall pre- and postoperative plasma Bmi1 mRNA level (31.73±2.63 vs. 31.93±2.88, respectively; P=0.614) in 45 CRC patients. However, when grouped into non-metastatic and metastatic CRC patients, the postoperative Bmi1 transcript level was found to be significantly lower compared to the preoperative level in patients with non-metastatic CRC (32.13±2.677 31.44±2.764, respectively; P=0.041), whereas there was a trend towards a higher postoperative Bmi1 transcript level compared to the preoperative level in the metastatic counterpart (30.85±3.916 vs. 33.27±0.718, respectively; P=0.164). Furthermore, when the patients were categorized into two groups according to their plasma Bmi1 postoperative vs. preoperative level status, we observed that patients without a reduction in the postoperative plasma Bmi1 mRNA levels exhibited a significantly higher rate of distant metastasis following primary resection (P=0.017) and a significantly worse prognosis regarding disease-free survival (P=0.016) when compared to the reduced postoperative plasma Bmi1 level counterparts. In conclusion, plasma Bmi1 mRNA levels may serve as a non-invasive biomarker for monitoring occult metastasis and predicting the development of distant metastasis.
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Affiliation(s)
| | | | | | - Ka-Wai Ng
- The Chinese Foundation Secondary School, Hong Kong, SAR, P.R. China
| | | | - Timothy Ming-Hun Wan
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China
| | - Oswens Lo
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China
| | - Jensen Tung-Chung Poon
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China
| | - Roberta Pang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China ; Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China
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44
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Wu SQ, Xu ZZ, Niu WY, Huang HB, Zhan R. ShRNA-mediated Bmi-1 silencing sensitizes multiple myeloma cells to bortezomib. Int J Mol Med 2014; 34:616-23. [PMID: 24913180 DOI: 10.3892/ijmm.2014.1798] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 04/29/2014] [Indexed: 11/05/2022] Open
Abstract
The introduction of bortezomib has resulted in a paradigm shift in the treatment of multiple myeloma (MM) and has contributed to the improved survival of patients with MM. Inevitably, resistance to therapy develops, and thus the clinical efficacy of bortezomib is hampered by drug resistance. The oncogene B-cell‑specific Moloney murine leukemia virus insertion site‑1 (Bmi-1) has been implicated in the pathogenesis of various human malignancies. Furthermore, RNA interference (RNAi)‑mediated Bmi-1 silencing has been shown to sensitize tumor cells to chemotherapy and radiation. The role of Bmi-1 in influencing the response to bortezomib therapy has not been investigated to date. In the present study, Bmi-1 was silenced in two MM cell lines (U266 and RPMI8226) using short hairpin RNA (shRNA) targeting Bmi-1 (shBmi-1). A cell counting kit-8 (CCK-8) assay was performed to analyze cell proliferation and evaluate the 50% inhibitory concentration (IC50) values of bortezomib. Cell cycle progression and apoptosis were analyzed by flow cytometry (FCM), and the mRNA and protein expression of associated genes (Bmi-1, p14, p21, Bcl-2 and Bax) was quantified by RT-qPCR and western blot analysis, respectively. The IC50 values significantly decreased in the cells transfected with shBmi-1 (p<0.05). The depletion of Bmi-1 sensitized the MM cells to bortezomib, which increased the G1 phase duration and enhanced bortezomib‑induced apoptosis (p<0.05). The expression of p21 and Bax (apoptosis inducer) was upregulated, whereas that of the anti-apoptotic protein, Bcl-2, was downregulated in the Bmi-1‑silenced cells (p<0.05). The depletion of Bmi-1 enhanced the sensitivity of MM cells to bortezomib by inhibiting cell proliferation and inducing cell cycle arrest and apoptosis. Our data suggest that Bmi-1 may serve as an important novel therapeutic target in MM.
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Affiliation(s)
- Shun-Quan Wu
- Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology, Fuzhou, Fujian 350001, P.R. China
| | - Zhen-Zhen Xu
- Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology, Fuzhou, Fujian 350001, P.R. China
| | - Wen-Yan Niu
- Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology, Fuzhou, Fujian 350001, P.R. China
| | - Hao-Bo Huang
- Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology, Fuzhou, Fujian 350001, P.R. China
| | - Rong Zhan
- Fujian Institute of Hematology, Affiliated Union Hospital of Fujian Medical University, Fujian Provincial Key Laboratory on Hematology, Fuzhou, Fujian 350001, P.R. China
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45
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Wei Y, Du Y, Chen X, Li P, Wang Y, Zang W, Zhao L, Li Z, Zhao G. Expression patterns of microRNA-218 and its potential functions by targeting CIP2A and BMI1 genes in melanoma. Tumour Biol 2014; 35:8007-15. [PMID: 24839010 DOI: 10.1007/s13277-014-2079-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 05/08/2014] [Indexed: 12/13/2022] Open
Abstract
Melanoma is the most aggressive skin cancer, and it is typically resistant or rapidly develops resistance to a variety of chemotherapeutic agents. microRNAs (miRNAs) play a part in the occurrence and development of malignant melanoma. In this study, we analyzed the miR-218 expression level in melanoma patients and cell lines and observed alterations in proliferation, cell cycle, migration, and invasion by increasing miR-218 expression in melanoma cell lines. We also performed bioinformatic analyses using TargetScan and miRanda and cloned both the wild-type and mutant versions of the human cancerous inhibitor of protein phosphatase 2A (CIP2A) and B lymphoma Mo-MLV insertion region 1 (BMI1) 3'-UTR fragments into the pmirGLO reporter vector. We then used the Dual-Luciferase assay system, quantitative real-time RT-PCR (qRT-PCR), and Western blot analysis to determine that miR-218 targeted the 3'-UTR of the oncogenes CIP2A and BMI1 and thus regulated the biological process of melanoma. We further demonstrated that CIP2A and BMI1 knockdown phenocopies miR-218 overexpression. In conclusion, our findings have shown that miR-218 is downregulated in melanoma. By targeting CIP2A and BMI1, miR-218 regulates the proliferation, migration, and invasion of the melanoma cell lines A375 and SK-MEL-2, indicating that miR-218 plays a pivotal role in melanoma development.
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Affiliation(s)
- Yanping Wei
- Department of Dermatology, The People's Hospital of Jiaozuo City, Jiaozuo, 454000, Henan, China
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Sartor ITS, Zeidán-Chuliá F, Albanus RD, Dalmolin RJS, Moreira JCF. Computational analyses reveal a prognostic impact of TULP3 as a transcriptional master regulator in pancreatic ductal adenocarcinoma. MOLECULAR BIOSYSTEMS 2014; 10:1461-8. [PMID: 24668219 DOI: 10.1039/c3mb70590k] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is recognized world-wide as an aggressive disease with poor prognosis in patients with or without resection. Further knowledge about the biological mechanisms of PDAC is necessary to enable the identification of novel molecular markers and therapeutic targets for early diagnosis and improved treatment. Transcription factors are the final effectors of signaling pathways and regulate a number of cellular functions. Changes in their expression may contribute to cellular transformation and tumor progression. Thus, the aim of the present study was to identify the Master Regulators (MRs) of transcription potentially involved in PDAC disease. To achieve this goal, we utilized microarray data to correlate MR genes with the tumor phenotype. Analyses were performed with RTN, Limma, and Survival packages in the R environment. We identified Tubby-like protein 3 (TULP3) as a MR of transcription in PDAC samples. The prognostic value of TULP3 was assessed in three independent cohort analyses. Our data demonstrated that pancreatic cancer patients exhibiting high transcriptional levels of TULP3 showed a poor overall survival rate. High expression levels of TULP3 may play an essential role in pancreatic cancer progression and possibly lead to a poor clinical outcome. Our results highlight the potential use of TULP3 as a clinical prognostic biomarker for pancreatic adenocarcinoma.
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Affiliation(s)
- I T S Sartor
- Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos 2600, Porto Alegre, RS CEP: 90035-003, Brazil.
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47
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Guo S, Xu X, Tang Y, Zhang C, Li J, Ouyang Y, Ju J, Bie P, Wang H. miR-15a inhibits cell proliferation and epithelial to mesenchymal transition in pancreatic ductal adenocarcinoma by down-regulating Bmi-1 expression. Cancer Lett 2014; 344:40-46. [DOI: 10.1016/j.canlet.2013.10.009] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 10/12/2013] [Accepted: 10/14/2013] [Indexed: 02/06/2023]
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48
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Quan M, Wang P, Cui J, Gao Y, Xie K. The roles of FOXM1 in pancreatic stem cells and carcinogenesis. Mol Cancer 2013; 12:159. [PMID: 24325450 PMCID: PMC3924162 DOI: 10.1186/1476-4598-12-159] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 11/28/2013] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses among all cancers. Over the past several decades, investigators have made great advances in the research of PDAC pathogenesis. Importantly, identification of pancreatic cancer stem cells (PCSCs) in pancreatic cancer cases has increased our understanding of PDAC biology and therapy. PCSCs are responsible for pancreatic tumorigenesis and tumor progression via a number of mechanisms, including extensive proliferation, self-renewal, high tumorigenic ability, high propensity for invasiveness and metastasis, and resistance to conventional treatment. Furthermore, emerging evidence suggests that PCSCs are involved in the malignant transformation of pancreatic intraepithelial neoplasia. The molecular mechanisms that control PCSCs are related to alterations of various signaling pathways, for instance, Hedgehog, Notch, Wnt, B-cell-specific Moloney murine leukemia virus insertion site 1, phosphoinositide 3-kinase/AKT, and Nodal/Activin. Also, authors have reported that the proliferation-specific transcriptional factor Forkhead box protein M1 is involved in PCSC self-renewal and proliferation. In this review, we describe the current knowledge about the signaling pathways related to PCSCs and the early stages of PDAC development, highlighting the pivotal roles of Forkhead box protein M1 in PCSCs and their impacts on the development and progression of pancreatic intraepithelial neoplasia.
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Affiliation(s)
| | | | | | | | - Keping Xie
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
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Yu J, Lu Y, Cui D, Li E, Zhu Y, Zhao Y, Zhao F, Xia S. miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1. Oncol Rep 2013; 31:910-8. [PMID: 24317363 DOI: 10.3892/or.2013.2897] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Accepted: 11/18/2013] [Indexed: 12/24/2022] Open
Abstract
microRNAs (miRNAs) are a class of small non-coding RNAs that can post-transcriptionally regulate gene expression and play critical roles in many important biological processes. The role of miRNAs in prostate cancer (PCa) development and pathogenesis remains largely unknown. In the present study, we showed that miR-200b was downregulated in clinical prostatic tumors when compared to normal prostate tissue and in advanced PCa cell lines when compared to normal epithelial prostatic cells. Enforced miR-200b expression suppressed PCa cell proliferation and migration and enhanced chemosensitivity to docetaxel by targeting B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1). Bmi-1 was detected at higher levels in PCa, and knockdown of Bmi-1 showed similar effects as miR-200b overexpression in PCa cells. Moreover, we confirmed that these effects were correlated with increased levels of E-cadherin and P16 and a reduction in vimentin expression and expression of stem cell markers (CD44 and OCT4). These findings suggest that miR-200b plays vital roles as a tumor-suppressor by targeting Bmi-1 and may be a promising therapeutic target for PCa treatment.
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Affiliation(s)
- Junjie Yu
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Youyi Lu
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Di Cui
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Enhui Li
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Yipin Zhu
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Yuyang Zhao
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Fujun Zhao
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Shujie Xia
- Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
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The components of Drosophila histone chaperone dCAF-1 are required for the cell death phenotype associated with rbf1 mutation. G3-GENES GENOMES GENETICS 2013; 3:1639-47. [PMID: 23893745 PMCID: PMC3789789 DOI: 10.1534/g3.113.007419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
A Polycomb group protein, Posterior sex combs (Psc), was identified in a genetic screen designed to find factors that can specifically induce morphological defects in rbf1 mutant eyes. We discovered that rbf1 mutations enhance developmental phenotypes caused by Psc overexpression such as ectopic cell death and disorganized ommatidia. Our genetic analysis revealed that Psc-induced developmental defects are strongly influenced by CAF1p55, which is a shared component of several chromatin-associated complexes including a histone chaperone complex, chromatin assembly factor-1 (dCAF-1). Interestingly, the expression levels of dCAF-1 components, CAF1p105 and CAF1p180, are increased in rbf1 mutants, whereas the expression level of CAF1p55 itself remains relatively unchanged. We demonstrated that the increased levels of CAF1p105 and CAF1p180 are required for the hypersensitivity of rbf1 mutant cells to Psc-induced cell death and for the developmentally regulated cell death normally observed in rbf1 mutant eyes. We propose that Caf1p105 and Caf1p180 are important determinants of cell death sensitivity in rbf1 mutant cells and contribute to the genetic interaction between Psc and rbf1.
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