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Ruan C, Shang T, Zhang S, Ru W, Yang Y, Shen Y. RIOK1: A Novel Oncogenic Driver in Hepatocellular Carcinoma. Cancer Med 2025; 14:e70597. [PMID: 39865406 PMCID: PMC11761428 DOI: 10.1002/cam4.70597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 06/18/2024] [Accepted: 06/27/2024] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common and highly lethal cancers worldwide. RIO kinase 1 (RIOK1), a protein kinase/ATPase that plays a key role in regulating translation and ribosome assembly, is associated with a variety of malignant tumors. However, the role of RIOK1 in HCC remains largely unknown. METHODS Changes in RIOK1 expression in HCC and patient prognosis were evaluated using HCC tissues and public databases. The functional role of RIOK1 in HCC was analyzed by RTCA assay, clonogenic assay, and flow cytometry in vitro, and by mouse tumor xenograft model in vivo. Potential mechanism studies were performed using multi-omics analysis, public database screening, and qRT-PCR assay. RESULTS In this study, we found that RIOK1 was elevated in HCC tissues and correlated with poor prognosis. Functional assays demonstrated that RIOK1 knockdown suppressed HCC cell proliferation, survival, and tumor growth in vivo, while RIOK1 overexpression enhanced these oncogenic phenotypes. Meanwhile, RIOK1 knockdown affected cell cycle progression and the expression of cyclin A2 and cyclin B1. Furthermore, integrated transcriptomic and proteomic analysis revealed that RIOK1 may promote HCC cell proliferation by affecting the cell cycle and DNA repair pathways. Moreover, we identified five potential effectors regulated by RIOK1: PMS1, SPDL1, RAD18, BARD1, and SMARCA5, which were highly expressed in HCC tissues and negatively correlated with the overall survival of HCC patients. CONCLUSION Our findings suggest that RIOK1 is a novel oncogenic driver that may serve as a potential diagnostic and therapeutic target for HCC.
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Affiliation(s)
- Chunyan Ruan
- Centre for Medical ResearchNingbo No.2 HospitalNingboChina
| | - Tianyu Shang
- Guoke Ningbo Life Science and Health Industry Research InstituteNingboChina
| | - Sijia Zhang
- Centre for Medical ResearchNingbo No.2 HospitalNingboChina
| | - Wenhong Ru
- Centre for Medical ResearchNingbo No.2 HospitalNingboChina
| | - Yuefeng Yang
- Centre for Medical ResearchNingbo No.2 HospitalNingboChina
| | - Yi Shen
- Centre for Medical ResearchNingbo No.2 HospitalNingboChina
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Stoler-Barak L, Schmiedel D, Sarusi-Portuguez A, Rogel A, Blecher-Gonen R, Haimon Z, Stopka T, Shulman Z. SMARCA5-mediated chromatin remodeling is required for germinal center formation. J Exp Med 2024; 221:e20240433. [PMID: 39297882 PMCID: PMC11413417 DOI: 10.1084/jem.20240433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 06/19/2024] [Accepted: 08/15/2024] [Indexed: 09/26/2024] Open
Abstract
The establishment of long-lasting immunity against pathogens is facilitated by the germinal center (GC) reaction, during which B cells increase their antibody affinity and differentiate into antibody-secreting cells (ASC) and memory cells. These events involve modifications in chromatin packaging that orchestrate the profound restructuring of gene expression networks that determine cell fate. While several chromatin remodelers were implicated in lymphocyte functions, less is known about SMARCA5. Here, using ribosomal pull-down for analyzing translated genes in GC B cells, coupled with functional experiments in mice, we identified SMARCA5 as a key chromatin remodeler in B cells. While the naive B cell compartment remained unaffected following conditional depletion of Smarca5, effective proliferation during B cell activation, immunoglobulin class switching, and as a result GC formation and ASC differentiation were impaired. Single-cell multiomic sequencing analyses revealed that SMARCA5 is crucial for facilitating the transcriptional modifications and genomic accessibility of genes that support B cell activation and differentiation. These findings offer novel insights into the functions of SMARCA5, which can be targeted in various human pathologies.
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Affiliation(s)
- Liat Stoler-Barak
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Dominik Schmiedel
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Avital Sarusi-Portuguez
- Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Adi Rogel
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ronnie Blecher-Gonen
- The Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Zhana Haimon
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Tomas Stopka
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Ziv Shulman
- Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel
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Wang K, Liu F, Muchu B, Deng J, Peng J, Xu Y, Li F, Ouyang M. E3 ubiquitin ligase RNF180 mediates the ALKBH5/SMARCA5 axis to promote colon inflammation and Th17/Treg imbalance in ulcerative colitis mice. Arch Pharm Res 2024; 47:645-658. [PMID: 39060657 DOI: 10.1007/s12272-024-01507-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 07/06/2024] [Indexed: 07/28/2024]
Abstract
SMARCA5, a protein in the SWI/SNF family, has been previously implicated in the development of ulcerative colitis (UC) through methylation. However, the specific molecular mechanisms by which SMARCA5 contributes to colonic inflammation and the imbalance between Th17 and Treg cells remain unclear. This study was designed to explore these molecular mechanisms. A UC mouse model was established using dextran sulfate sodium induction, followed by measurements of mouse weight, disease activity index (DAI) score, colon length, pathological changes in the colon, and FITC-dextran concentration. The levels of IL-17a, IFN-γ, IL-6, TNF-α, TGF-β, and IL-10 were measured, along with the protein expression of ZO-1 and Occludin. Flow cytometry was used to assess the presence of IL-17 + CD4 + (Th17 +) cells and FOXP3 + CD25 + CD4 + (Treg +) cells in the spleen and mesenteric lymph nodes of UC mice. We observed that SMARCA5 and RNF180 were increased, while ALKBH5 was downregulated in UC mouse colon tissue. SMARCA5 or RNF180 knockdown or ALKBH5 overexpression ameliorated the colon inflammation and Th17/Treg cell imbalance in UC mice, shown by increased body weight, colon length, FOXP3 + CD25 + CD4 + T cells, and the levels of ZO-1, Occludin, TGF-β, IL-10, and FOXP3. It decreased DAI scores, IL-17 + CD4 + T cells, and levels of IL-17a, IFN-γ, IL-6, TNF-α, and ROR-γt. ALKBH5 inhibited SMARCA5 expression via m6A modification, while RNF180 reduced ALKBH5 expression via ubiquitination. Our findings indicate that RNF180 aggravated the colon inflammation and Th17/Treg cell imbalance in UC mice by regulating the ALKBH5/SMARCA5 axis.
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MESH Headings
- Animals
- Male
- Mice
- AlkB Homolog 5, RNA Demethylase/metabolism
- Chromosomal Proteins, Non-Histone/metabolism
- Chromosomal Proteins, Non-Histone/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/pathology
- Colitis, Ulcerative/chemically induced
- Colitis, Ulcerative/metabolism
- Dextran Sulfate/toxicity
- Disease Models, Animal
- Inflammation/metabolism
- Inflammation/pathology
- Inflammation/immunology
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitin-Protein Ligases/genetics
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Affiliation(s)
- Kailing Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Fan Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Budumu Muchu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Jiawen Deng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Jing Peng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Yan Xu
- Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Fujun Li
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China
| | - Miao Ouyang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
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Zhang FL, Li DQ. Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy. Int J Mol Sci 2022; 23:12815. [PMID: 36361605 PMCID: PMC9655648 DOI: 10.3390/ijms232112815] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/12/2022] [Accepted: 10/19/2022] [Indexed: 03/28/2024] Open
Abstract
ATP-dependent chromatin-remodeling complexes can reorganize and remodel chromatin and thereby act as important regulator in various cellular processes. Based on considerable studies over the past two decades, it has been confirmed that the abnormal function of chromatin remodeling plays a pivotal role in genome reprogramming for oncogenesis in cancer development and/or resistance to cancer therapy. Recently, exciting progress has been made in the identification of genetic alteration in the genes encoding the chromatin-remodeling complexes associated with tumorigenesis, as well as in our understanding of chromatin-remodeling mechanisms in cancer biology. Here, we present preclinical evidence explaining the signaling mechanisms involving the chromatin-remodeling misregulation-induced cancer cellular processes, including DNA damage signaling, metastasis, angiogenesis, immune signaling, etc. However, even though the cumulative evidence in this field provides promising emerging molecules for therapeutic explorations in cancer, more research is needed to assess the clinical roles of these genetic cancer targets.
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Affiliation(s)
- Fang-Lin Zhang
- Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Da-Qiang Li
- Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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The Emerging Roles and Clinical Potential of circSMARCA5 in Cancer. Cells 2022; 11:cells11193074. [PMID: 36231036 PMCID: PMC9562909 DOI: 10.3390/cells11193074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/25/2022] [Accepted: 09/26/2022] [Indexed: 12/24/2022] Open
Abstract
Circular RNAs (circRNAs) are a type of endogenous non-coding RNA and a critical epigenetic regulation way that have a closed-loop structure and are highly stable, conserved, and tissue-specific, and they play an important role in the development of many diseases, including tumors, neurological diseases, and cardiovascular diseases. CircSMARCA5 is a circRNA formed by its parental gene SMARCA5 via back splicing which is dysregulated in expression in a variety of tumors and is involved in tumor development with dual functions as an oncogene or tumor suppressor. It not only serves as a competing endogenous RNA (ceRNA) by binding to various miRNAs, but it also interacts with RNA binding protein (RBP), regulating downstream gene expression; it also aids in DNA damage repair by regulating the transcription and expression of its parental gene. This review systematically summarized the expression and characteristics, dual biological functions, and molecular regulatory mechanisms of circSMARCA5 involved in carcinogenesis and tumor progression as well as the potential applications in early diagnosis and gene targeting therapy in tumors.
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Xu Y, Yang J, Chen X, Deng J, Gong H, Li F, Ouyang M. MicroRNA-182-5p aggravates ulcerative colitis by inactivating the Wnt/β-catenin signaling pathway through DNMT3A-mediated SMARCA5 methylation. Genomics 2022; 114:110360. [PMID: 35378241 DOI: 10.1016/j.ygeno.2022.110360] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 03/16/2022] [Accepted: 03/29/2022] [Indexed: 01/14/2023]
Abstract
This research focused on novel molecular mechanisms underlying microRNA (miR)-182-5p in ulcerative colitis (UC). Colon tissues were obtained from UC patients, and dextrose sodium sulfate (DSS)-induced mouse and interleukin-1β (IL-1β)-induced Caco-2 cell models were generated. Then, miR-182-5p, SMARCA5, and the Wnt/β-catenin signaling pathway were altered in IL-1β-stimulated Caco-2 cells and DSS-treated mice to assess their function. MiR-182-5p and SMARCA5 were upregulated and DNMT3A, β-catenin, and Cyclin D1 were downregulated in UC patients, IL-1β-stimulated Caco-2 cells, and DSS-treated mice. Mechanistically, miR-182-5p targeted DNMT3A to upregulate SMARCA5, thus blocking the Wnt/β-catenin signaling pathway. Moreover, SMARCA5 silencing or Wnt/β-catenin signaling pathway activation repressed apoptosis and augmented proliferation and epithelial barrier function of IL-1β-stimulated Caco-2 cells. SMARCA5 silencing annulled the impacts of miR-182-5p overexpression on IL-1β-stimulated Caco-2 cells. SMARCA5 silencing or miR-182-5p inhibition ameliorated intestinal barrier dysfunction in DSS-treated mice. Collectively, miR-182-5p aggravates UC by inactivating the Wnt/β-catenin signaling pathway through DNMT3A-mediated SMARCA5 methylation.
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Affiliation(s)
- Yan Xu
- Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Junwen Yang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Xiaoli Chen
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Jiawen Deng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Hui Gong
- Department of Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Fujun Li
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
| | - Miao Ouyang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
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Thakur S, Cahais V, Turkova T, Zikmund T, Renard C, Stopka T, Korenjak M, Zavadil J. Chromatin Remodeler Smarca5 Is Required for Cancer-Related Processes of Primary Cell Fitness and Immortalization. Cells 2022; 11:808. [PMID: 35269430 PMCID: PMC8909548 DOI: 10.3390/cells11050808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/19/2022] [Accepted: 02/22/2022] [Indexed: 12/04/2022] Open
Abstract
Smarca5, an ATPase of the ISWI class of chromatin remodelers, is a key regulator of chromatin structure, cell cycle and DNA repair. Smarca5 is deregulated in leukemia and breast, lung and gastric cancers. However, its role in oncogenesis is not well understood. Chromatin remodelers often play dosage-dependent roles in cancer. We therefore investigated the epigenomic and phenotypic impact of controlled stepwise attenuation of Smarca5 function in the context of primary cell transformation, a process relevant to tumor formation. Upon conditional single- or double-allele Smarca5 deletion, the cells underwent both accelerated growth arrest and senescence entry and displayed gradually increased sensitivity to genotoxic insults. These phenotypic characteristics were explained by specific remodeling of the chromatin structure and the transcriptome in primary cells prior to the immortalization onset. These molecular programs implicated Smarca5 requirement in DNA damage repair, telomere maintenance, cell cycle progression and in restricting apoptosis and cellular senescence. Consistent with the molecular programs, we demonstrate for the first time that Smarca5-deficient primary cells exhibit dramatically decreased capacity to bypass senescence and immortalize, an indispensable step during cell transformation and cancer development. Thus, Smarca5 plays a crucial role in key homeostatic processes and sustains cancer-promoting molecular programs and cellular phenotypes.
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Affiliation(s)
- Shefali Thakur
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, 69008 Lyon, France; (S.T.); (V.C.); (C.R.)
- Faculty of Science, Charles University, 128 43 Prague, Czech Republic; (S.T.)
- Biocev, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic; (T.T.); (T.Z.); (T.S.)
| | - Vincent Cahais
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, 69008 Lyon, France; (S.T.); (V.C.); (C.R.)
| | - Tereza Turkova
- Biocev, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic; (T.T.); (T.Z.); (T.S.)
| | - Tomas Zikmund
- Biocev, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic; (T.T.); (T.Z.); (T.S.)
- Institute of Epigenetics and Stem Cells (IES), Helmholtz Zentrum, D-81377 München, Germany; (T.Z.)
| | - Claire Renard
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, 69008 Lyon, France; (S.T.); (V.C.); (C.R.)
| | - Tomáš Stopka
- Biocev, First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic; (T.T.); (T.Z.); (T.S.)
| | - Michael Korenjak
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, 69008 Lyon, France; (S.T.); (V.C.); (C.R.)
| | - Jiri Zavadil
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, 69008 Lyon, France; (S.T.); (V.C.); (C.R.)
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Identification of Predictive Biomarkers of Response to HSP90 Inhibitors in Lung Adenocarcinoma. Int J Mol Sci 2021; 22:ijms22052538. [PMID: 33802597 PMCID: PMC7962034 DOI: 10.3390/ijms22052538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/19/2021] [Accepted: 02/27/2021] [Indexed: 12/17/2022] Open
Abstract
Heat shock protein 90 (HSP90) plays an essential role in lung adenocarcinoma, acting as a key chaperone involved in the correct functioning of numerous highly relevant protein drivers of this disease. To this end, HSP90 inhibitors have emerged as promising therapeutic strategies, even though responses to them have been limited to date. Given the need to maximize treatment efficacy, the objective of this study was to use isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic techniques to identify proteins in human lung adenocarcinoma cell lines whose basal abundances were correlated with response to HSP90 inhibitors (geldanamycin and radicicol derivatives). From the protein profiles identified according to response, the relationship between lactate dehydrogenase B (LDHB) and DNA topoisomerase 1 (TOP1) with respect to sensitivity and resistance, respectively, to geldanamycin derivatives is noteworthy. Likewise, rhotekin (RTKN) and decaprenyl diphosphate synthase subunit 2 (PDSS2) were correlated with sensitivity and resistance to radicicol derivatives. We also identified a relationship between resistance to HSP90 inhibition and the p53 pathway by glucose deprivation. In contrast, arginine biosynthesis was correlated with sensitivity to HSP90 inhibitors. Further study of these outcomes could enable the development of strategies to improve the clinical efficacy of HSP90 inhibition in patients with lung adenocarcinoma.
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9
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Li L, Zhu H, Li X, Ke Y, Yang S, Cheng Q. Long non-coding RNA HAGLROS facilitates the malignant phenotypes of NSCLC cells via repressing miR-100 and up-regulating SMARCA5. Biomed J 2020; 44:S305-S315. [PMID: 35307327 PMCID: PMC9068548 DOI: 10.1016/j.bj.2020.12.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 12/15/2020] [Accepted: 12/24/2020] [Indexed: 12/25/2022] Open
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10
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Xu X, Zhang J, Tian Y, Gao Y, Dong X, Chen W, Yuan X, Yin W, Xu J, Chen K, He C, Wei L. CircRNA inhibits DNA damage repair by interacting with host gene. Mol Cancer 2020; 19:128. [PMID: 32838810 PMCID: PMC7446195 DOI: 10.1186/s12943-020-01246-x] [Citation(s) in RCA: 233] [Impact Index Per Article: 46.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/12/2020] [Indexed: 01/01/2023] Open
Abstract
Background Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. Method We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. Results We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. Conclusion Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.
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Affiliation(s)
- Xiaolong Xu
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
| | - Jingwei Zhang
- Hubei Key Laboratory of Tumor Biological Behaviors, Department of Breast and Thyroid Surgery, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Yihao Tian
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
| | - Yang Gao
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
| | - Xin Dong
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
| | - Wenbo Chen
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
| | - Xiaoning Yuan
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
| | - Weinan Yin
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China
| | - Jinjing Xu
- Hubei Key Laboratory of Tumor Biological Behaviors, Department of Breast and Thyroid Surgery, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China
| | - Ke Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Chunjiang He
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China. .,College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China.
| | - Lei Wei
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei, China. .,Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, 430071, Hubei, China.
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MiR-146b-5p suppresses the malignancy of GSC/MSC fusion cells by targeting SMARCA5. Aging (Albany NY) 2020; 12:13647-13667. [PMID: 32632040 PMCID: PMC7377863 DOI: 10.18632/aging.103489] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023]
Abstract
Recent studies have confirmed that both cancer-associated bone marrow mesenchymal stem cells (BM-MSCs, MSCs) and glioma stem-like cells (GSCs) contribute to malignant progression of gliomas through their mutual interactions within the tumor microenvironment. However, the exact ways and relevant mechanisms involved in the actions of GSCs and MSCs within the glioma microenvironment are not fully understood. Using a dual-color fluorescence tracing model, our studies revealed that GSCs are able to spontaneously fuse with MSCs, yielding GSC/MSC fusion cells, which exhibited markedly enhanced proliferation and invasiveness. MiR-146b-5p was downregulated in the GSC/MSC fusion cells, and its overexpression suppressed proliferation, migration and invasion by the fusion cells. SMARCA5, which is highly expressed in high-grade gliomas, was a direct downstream target of miR-146b-5p in the GSC/MSC fusion cells. miR-146b-5p inhibited SMARCA5 expression and inactivated a TGF-β pathway, thereby decreasing GSC/MSC fusion cell proliferation, migration and invasion. Collectively, these findings demonstrate that miR-146b-5p suppresses the malignant phenotype of GSC/MSC fusion cells in the glioma microenvironment by targeting a SMARCA5-regulated TGF-β pathway.
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12
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Abstract
The SMARCA subgroup of genes belong to the SWI1/SNF1 family that are responsible chromatin remodelling and repair. Inactivating mutations in the main SMARCA genes A2 and A4 lead to loss of expression of their respective proteins within the nucleus and, as such have characterised a set of malignancies that are underpinned by SMARCA-deficiency.The morphology of these tumours ranges from small to large epithelioid cells, giant cells and rhabdoid cells. The rhabdoid cells are frequently present in these tumours but are not a sine qua non for the diagnosis. Most of these tumours are undifferentiated or dedifferentiated, high-grade pleomorphic carcinomas. Focally, areas of better differentiation can be seen. The initial description of a SMARCA4-deficient malignancy was the small cell carcinoma of the ovary, hypercalcaemic type. Subsequently, tumours fitting this characteristic morphology and immunophenotype have been described in the lung, thoracic cavity, endometrium and sinonasal tract, gastrointestinal tract and kidney. Immunohistochemical loss of SMARCA2 and SMARCA4 may occur concomitantly or independently of each other.SMARCA-deficient malignant tumours represent a unique subset of tumours with typical morphological and immunohistochemical findings.
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Affiliation(s)
- Runjan Chetty
- Department of Pathology, University Health Network Laboratory Medicine Program, University of Toronto, Toronto, Ontario, Canada
| | - Stefano Serra
- Department of Pathology, University Health Network Laboratory Medicine Program, University of Toronto, Toronto, Ontario, Canada
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13
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Loss of ISWI ATPase SMARCA5 (SNF2H) in Acute Myeloid Leukemia Cells Inhibits Proliferation and Chromatid Cohesion. Int J Mol Sci 2020; 21:ijms21062073. [PMID: 32197313 PMCID: PMC7139293 DOI: 10.3390/ijms21062073] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/11/2020] [Accepted: 03/16/2020] [Indexed: 01/27/2023] Open
Abstract
ISWI chromatin remodeling ATPase SMARCA5 (SNF2H) is a well-known factor for its role in regulation of DNA access via nucleosome sliding and assembly. SMARCA5 transcriptionally inhibits the myeloid master regulator PU.1. Upregulation of SMARCA5 was previously observed in CD34+ hematopoietic progenitors of acute myeloid leukemia (AML) patients. Since high levels of SMARCA5 are necessary for intensive cell proliferation and cell cycle progression of developing hematopoietic stem and progenitor cells in mice, we reasoned that removal of SMARCA5 enzymatic activity could affect the cycling or undifferentiated state of leukemic progenitor-like clones. Indeed, we observed that CRISPR/cas9-mediated SMARCA5 knockout in AML cell lines (S5KO) inhibited the cell cycle progression. We also observed that the SMARCA5 deletion induced karyorrhexis and nuclear budding as well as increased the ploidy, indicating its role in mitotic division of AML cells. The cytogenetic analysis of S5KO cells revealed the premature chromatid separation. We conclude that deleting SMARCA5 in AML blocks leukemic proliferation and chromatid cohesion.
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14
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Ai C, Ma G, Deng Y, Zheng Q, Gen Y, Li W, Li Y, Zu L, Zhou Q. Nm23-H1 inhibits lung cancer bone-specific metastasis by upregulating miR-660-5p targeted SMARCA5. Thorac Cancer 2020; 11:640-650. [PMID: 32022430 PMCID: PMC7049508 DOI: 10.1111/1759-7714.13308] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/23/2019] [Accepted: 12/27/2019] [Indexed: 02/05/2023] Open
Abstract
Background Nm23‐H1 gene has been found to be an inhibitor of tumor metastasis in lung cancer. MicroRNAs (miRNAs) play key roles in tumor metastasis through multiple signaling pathways. This study explored whether the nm23‐H1 gene could inhibit invasion and metastasis of lung cancer cells by regulating miRNA‐660‐5p targets. Methods Quantitative real‐time PCR (qRT‐PCR) and western blots were used to measure the expression of nm23‐H1 and miR‐660‐5p of various human lung cancer cell lines. Cell counting kit‐8 (CCK‐8), wound‐healing and transwell assay were carried out to assess cell proliferation, migration and invasion of each cell line. Xenograft were applied to determine in vivo effects of miR‐660‐5p among nude mice. Luciferase assay and western blot were performed to determine the target gene of miR‐660‐5p. Results We found that high expression of nm23‐H1 correlated with decreased miRNA‐660‐5p expression. Inhibiting miR‐660‐5p suppressed lung cancer cells progression significantly in vitro, whereas overexpression of miR‐660‐5p facilitated tumor growth and bone metastasis in vivo. In addition, as the potential target gene of miR‐660‐5p, SMARCA5 overexpression in vitro suppressed tumor progression and osteolytic metastasis associated RANKL signaling, which is congruent with the effect of nm23‐H1 on the lung cancer cells. Conclusion Nm23‐H1 inhibits tumor progression and bone‐specific metastasis of lung cancer by regulating miR‐660‐5p/SMARCA5/RANKL axis, which indicates the related genes may serve as potential targets for the treatment of human lung cancer. Key points Significant findings of the study High expression of nm23‐H1 correlated with decreased miRNA‐660‐5p expression. Further, downregulation of miR‐660‐5p significantly suppressed the tumor progression and bone‐specific metastasis of lung cancer cells. What this study adds This is the first study to show an inverse association between nm23‐H1 and miR‐660‐5p, and confirm that nm23‐H1 inhibits tumor progression and bone‐specific metastasis of lung cancer by regulating miR‐660‐5p/SMARCA5/RANKL axis.
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Affiliation(s)
- Cheng Ai
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,Department of Cardiothoracic Surgery, Panzhihua Central Hospital of Sichuan, Panzhihua, China
| | - Guangzhi Ma
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yunfu Deng
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiangqiang Zheng
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yingcai Gen
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wen Li
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingling Zu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Qinghua Zhou
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China.,Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
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15
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Abstract
MicroRNAs (miRNAs) are small, non-coding RNA molecules that inhibit protein translation from target mRNAs. Accumulating evidence suggests that miRNAs can regulate a broad range of biological pathways, including cell differentiation, apoptosis, and carcinogenesis. With the development of miRNAs, the investigation of miRNA functions has emerged as a hot research field. Due to the intensive farming in recent decades, chickens are easily influenced by various pathogen transmissions, and this has resulted in large economic losses. Recent reports have shown that miRNAs can play critical roles in the regulation of chicken diseases. Therefore, the aim of this review is to briefly discuss the current knowledge regarding the effects of miRNAs on chickens suffering from common viral diseases, mycoplasmosis, necrotic enteritis, and ovarian tumors. Additionally, the detailed targets of miRNAs and their possible functions are also summarized. This review intends to highlight the key role of miRNAs in regard to chickens and presents the possibility of improving chicken disease resistance through the regulation of miRNAs.
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16
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Alrfaei BM, Clark P, Vemuganti R, Kuo JS. MicroRNA miR-100 Decreases Glioblastoma Growth by Targeting SMARCA5 and ErbB3 in Tumor-Initiating Cells. Technol Cancer Res Treat 2020; 19:1533033820960748. [PMID: 32945237 PMCID: PMC7502994 DOI: 10.1177/1533033820960748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 08/12/2020] [Accepted: 08/28/2020] [Indexed: 01/09/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive and most frequently diagnosed malignant human glioma. Despite the best available standard of care (surgery, radiation, and chemotherapy), the median survival of GBM patients is less than 2 years. Many recent studies have indicated that microRNAs (miRNAs) are important for promoting or reducing/limiting GBM growth. In particular, we previously showed that GBMs express decreased levels of miR-100 relative to control tissue and that restoring miR-100 expression reduced GBM tumorigenicity by modulating SMRT/NCOR2 (Nuclear Receptor Corepressor 2). Here, we demonstrate that miR-100 overexpression decreases expression of the stem cell markers, nestin and L1CAM, and decreases proliferation of GBM tumor-initiating cells (cancer stem cells). We further show that miR-100-mediated anti-tumorigenic activity limits the activity of SMARCA5 and its downstream target STAT3 (known as mTOR-STAT3-Notch pathway). In addition, we report ErbB3 (Her3) as a putative miR-100 target, including inhibition of its downstream AKT and ERK signaling pathways.
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Affiliation(s)
- Bahauddeen M. Alrfaei
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Cellular and Molecular Pathology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Cellular Therapy and Cancer Res, King Abdullah Int’l Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
| | - Paul Clark
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Cellular and Molecular Pathology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - John S. Kuo
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Cellular and Molecular Pathology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
- Mulva Clinic for the Neurosciences, The University of Texas at Austin, Austin, TX, USA
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17
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Hasan N, Ahuja N. The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer. Cancers (Basel) 2019; 11:E1859. [PMID: 31769422 PMCID: PMC6966483 DOI: 10.3390/cancers11121859] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 02/08/2023] Open
Abstract
Pancreatic cancer is an aggressive cancer with low survival rates. Genetic and epigenetic dysregulation has been associated with the initiation and progression of pancreatic tumors. Multiple studies have pointed to the involvement of aberrant chromatin modifications in driving tumor behavior. ATP-dependent chromatin remodeling complexes regulate chromatin structure and have critical roles in stem cell maintenance, development, and cancer. Frequent mutations and chromosomal aberrations in the genes associated with subunits of the ATP-dependent chromatin remodeling complexes have been detected in different cancer types. In this review, we summarize the current literature on the genomic alterations and mechanistic studies of the ATP-dependent chromatin remodeling complexes in pancreatic cancer. Our review is focused on the four main subfamilies: SWItch/sucrose non-fermentable (SWI/SNF), imitation SWI (ISWI), chromodomain-helicase DNA-binding protein (CHD), and INOsitol-requiring mutant 80 (INO80). Finally, we discuss potential novel treatment options that use small molecules to target these complexes.
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Affiliation(s)
| | - Nita Ahuja
- Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA;
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18
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Tan Y, Zhang T, Liang C. Circular RNA SMARCA5 is overexpressed and promotes cell proliferation, migration as well as invasion while inhibits cell apoptosis in bladder cancer. Transl Cancer Res 2019; 8:1663-1671. [PMID: 35116915 PMCID: PMC8799073 DOI: 10.21037/tcr.2019.08.08] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 07/11/2019] [Indexed: 11/06/2022]
Abstract
Background This study aimed to investigate the function of circular RNA SMARCA5 (circ-SMARCA5) on cell proliferation, apoptosis, migration and invasion in bladder cancer. Methods Ten pairs of human bladder cancer tissue and adjacent tissue, five human bladder cancer cell lines (including TCCSUP, 5637, J82, UM-UC-3 and T-24) and normal human urothelial cell line SV-HUC-1, were obtained for the detection of circ-SMARCA5. Control overexpression and ShRNA, circ-SMARCA5 overexpression and ShRNA were constructed and transfected into UM-UC-3 cells as Control(+), Control(−), Circ-SMARCA5(+) and Circ-SMARCA5(−) groups. The role of circ-SMARCA5 was investigated in terms of cellular proliferation, apoptosis, migration, and invasion. Results Circ-SMARCA5 was overexpressed in tumor tissue compared to paired adjacent tissue and it was also overexpressed in TCCSUP, 5637, J82 and UM-UC-3 cells compared to normal human urothelial cell line SV-HUC-1. In UM-UC-3 cells, cell proliferation ability, migration rate and invasion cell count were increased in Circ-SMARCA5(+) group compared to Control(+) group, while reduced in Circ-SMARCA5(−) group compared to Control(−) group. Regarding the cell apoptosis, apoptosis rate and apoptotic protein C-Caspase 3 expression were decreased in Circ-SMARCA5(+) group than those in Control(+) group but raised in Circ-SMARCA5(−) group compared to Control(−) group, meanwhile, the anti-apoptotic protein Bcl-2 expression was elevated in Circ-SMARCA5(+) group than that in Control(+) group but reduced in Circ-SMARCA5(−) group compared to Control(−) group. Conclusions Circ-SMARCA5 is overexpressed, and promotes cell proliferation, migration and invasion, but represses apoptosis in bladder cancer.
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Affiliation(s)
- Yiao Tan
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.,Institute of Urology, Anhui Medical University, Hefei 230022, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China.,Department of Urology, West Branch of the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, China
| | - Tengyue Zhang
- Department of Oncology, West Branch of the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, China
| | - Chaozhao Liang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.,Institute of Urology, Anhui Medical University, Hefei 230022, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230022, China
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19
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Advances of circular RNAs in carcinoma. Biomed Pharmacother 2018; 107:59-71. [PMID: 30077838 DOI: 10.1016/j.biopha.2018.07.164] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/29/2018] [Accepted: 07/31/2018] [Indexed: 12/14/2022] Open
Abstract
Circular RNAs (circRNAs) are a type of non-coding RNAs with single-stranded closed structure. The rapid development of high-throughput sequencing technology has allowed for the widespread presence of circRNAs in transcriptomes. Moreover, increasing studies have identified a correlation between circRNAs and different cancers. In addition, most circRNAs are dysregulated in various cancers, and some of them have been reported be vital in the occurrence and development of tumors. For example, ciRS-7 plays a role in tumor promotion and circ-ITCH acts as a tumor suppressor. This review summarizes the latest progressions in the field regarding the functions of circRNAs in relation with cancers, and anticipates the emerging roles of circRNAs and future challenges in cancer research.
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20
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Yu J, Xu QG, Wang ZG, Yang Y, Zhang L, Ma JZ, Sun SH, Yang F, Zhou WP. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J Hepatol 2018; 68:1214-1227. [PMID: 29378234 DOI: 10.1016/j.jhep.2018.01.012] [Citation(s) in RCA: 545] [Impact Index Per Article: 77.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 12/27/2017] [Accepted: 01/06/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS In recent years, circular RNAs (circRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of circRNAs to hepatocellular carcinoma (HCC) remain largely unknown. METHODS cSMARCA5 (a circRNA derived from exons 15 and 16 of the SMARCA5 gene, hsa_circ_0001445) was identified by RNA-sequencing and validated by quantitative reverse transcription PCR. The role of cSMARCA5 in HCC progression was assessed both in vitro and in vivo. circRNAs in vivo precipitation, luciferase reporter assay, biotin-coupled microRNA capture and fluorescence in situ hybridization were conducted to evaluate the interaction between cSMARCA5 and miR-17-3p/miR-181b-5p. RESULTS The expression of cSMARCA5 was lower in HCC tissues, because of the regulation of DExH-Box Helicase 9, an abundant nuclear RNA helicase. The downregulation of cSMARCA5 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival and recurrence-free survival in patients with HCC after hepatectomy. Our in vivo and in vitro data indicated that cSMARCA5 inhibits the proliferation and migration of HCC cells. Mechanistically, we found that cSMARCA5 could promote the expression of TIMP3, a well-known tumor suppressor, by sponging miR-17-3p and miR-181b-5p. CONCLUSION These results reveal an important role of cSMARCA5 in the growth and metastasis of HCC and provide a fresh perspective on circRNAs in HCC progression. LAY SUMMARY Herein, we studied the role of cSMARCA5, a circular RNA, in hepatocellular carcinoma. Our in vitro and in vivo data showed that cSMARCA5 inhibits the growth and migration of hepatocellular carcinoma cells, making it a potential therapeutic target.
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Affiliation(s)
- Jian Yu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Qing-Guo Xu
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhen-Guang Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ling Zhang
- The Department of Medical Genetics, Second Military Medical University, Shanghai, China
| | - Jin-Zhao Ma
- The Department of Medical Genetics, Second Military Medical University, Shanghai, China
| | - Shu-Han Sun
- The Department of Medical Genetics, Second Military Medical University, Shanghai, China
| | - Fu Yang
- The Department of Medical Genetics, Second Military Medical University, Shanghai, China.
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
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21
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Ko EA, Sanders KM, Zhou T. A transcriptomic insight into the impacts of mast cells in lung, breast, and colon cancers. Oncoimmunology 2017; 6:e1360457. [PMID: 29147625 DOI: 10.1080/2162402x.2017.1360457] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 07/20/2017] [Accepted: 07/21/2017] [Indexed: 01/09/2023] Open
Abstract
To date, the exact impact of mast cells in tumor microenvironment is still controversial because of inconsistency in observations regarding the relationship between mast cell infiltrates and cancer development and prognosis. The discrepancies in previous studies have motivated us to examine the roles of mast cells in cancer pathology from different perspectives. Here, we investigated the impact of mast cells on transcriptomic profiles in the tissue microenvironment. Mice carrying the W-sh mutation in c-kit (KitW-sh ) are deficient in mast cell production and were used to assess the influence of mast cells on gene expression. By examining the transcriptomic profile among wild-type mice, KitW-sh mice, and KitW-sh mice with mast cell engraftment, we identified a list of "mast cell-dependent genes," which are enriched for cancer-related pathways. Utilizing whole-genome gene expression data from both mouse models and human cancer patients, we demonstrated that the expression profile of the mast cell-dependent genes differs between tumor and normal tissues from lung, breast, and colon, respectively. Mast cell infiltration is potentially increased in tumors compared with normal tissues, suggesting that mast cells might participate in tumor development. Accordingly, a prognostic molecular signature was developed based on the mast cell-dependent genes, which predicted recurrence-free survival for human patients with lung, breast, and colon cancers, respectively. Our study provides a novel transcriptomic insight into the impact of mast cells in the tumor microenvironment, though further experimental investigation is needed to validate the exact role of individual mast cell-dependent genes in different cancers.
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Affiliation(s)
- Eun-A Ko
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada, USA
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada, USA
| | - Tong Zhou
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada, USA
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22
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Zhao Y, Wang Z, Hou Y, Zhang K, Peng X. gga-miR-99a targets SMARCA5 to regulate Mycoplasma gallisepticum (HS strain) infection by depressing cell proliferation in chicken. Gene 2017; 627:239-247. [PMID: 28652181 DOI: 10.1016/j.gene.2017.06.039] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 06/16/2017] [Accepted: 06/20/2017] [Indexed: 10/19/2022]
Abstract
Mycoplasma gallisepticum (MG), one of the primary etiological agents of poultry chronic respiratory disease, has caused significant economic losses worldwide, and increasing evidence has recently indicated that miRNAs are involved in its microbial pathogenesis. gga-miR-99a, a member of the miR-99 family, plays an essential role in a variety of diseases. Through miRNA Solexa sequencing, we previously found that gga-miR-99a is significantly down-regulated in the lungs of MG-infected chicken embryos. In this study, we further verified that the expression of gga-miR-99 was significantly down-regulated in both MG-infected lungs and a chicken embryonic fibroblast cell line (DF-1) by qPCR. Moreover, we predicted and validated SMARCA5 as its target gene through a luciferase reporter assay, qPCR, and western blot analysis. The over-expression of gga-miR-99a significantly depressed SMARCA5 expression, whereas a gga-miR-99a inhibitor enhanced the expression of SMARCA5. Inversely, SMARCA5 was significantly up-regulated and gga-miR-99a was obviously down-regulated in MG-HS-infected chicken embryonic lungs and DF-1 cells. At 72h post-transfection, the over-expression of gga-miR-99a significantly repressed the proliferation of DF-1 cells by inhibiting the transition from the G1 phase to the S and G2 phases. This study reveals that gga-miR-99a plays a key role in MG infection through the regulation of SMARCA5 expression and provides new insights regarding the mechanisms of MG pathogenesis.
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Affiliation(s)
- Yabo Zhao
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Zaiwei Wang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Yue Hou
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Kang Zhang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiuli Peng
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
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23
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Zeng XQ, Wang J, Chen SY. Methylation modification in gastric cancer and approaches to targeted epigenetic therapy (Review). Int J Oncol 2017; 50:1921-1933. [DOI: 10.3892/ijo.2017.3981] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 03/22/2017] [Indexed: 11/06/2022] Open
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24
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Wang Y, Qin J, Liu Q, Hong X, Li T, Zhu Y, He L, Zheng B, Li M. SNF2H promotes hepatocellular carcinoma proliferation by activating the Wnt/β-catenin signaling pathway. Oncol Lett 2016; 12:1329-1336. [PMID: 27446433 PMCID: PMC4950594 DOI: 10.3892/ol.2016.4681] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 05/10/2016] [Indexed: 01/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. Surgical resection is always inapplicable to HCC patients diagnosed at an advanced tumor stage. The mechanisms underlying HCC cell proliferation remain obscure. In the present study, SWItch/sucrose nonfermentable catalytic subunit SNF2 (SNF2H) expression was tested in HCC tissues and Wnt/β-catenin pathway activation upon overexpression of SNF2H or knockdown of SNF2H expression was investigated in cultured HCC cells. It was demonstrated that SNF2H is a vital factor for HCC growth. The SNF2H expression level is increased in HCC tissues compared with paratumoral liver tissues. SNF2H promotes HCC cell proliferation and colony formation ability in vitro. SNF2H may increase the protein level of β-catenin and enhance its nuclear accumulation in HCC cells, thereby leading to the activation of the Wnt/β-catenin signaling pathway. In conclusion, the present results indicate that SNF2H plays a vital role in HCC cell growth, suggesting that SNF2H may be a promising therapeutic target for HCC treatment.
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Affiliation(s)
- Yanan Wang
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Juanxiu Qin
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Qian Liu
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Xufen Hong
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Tianming Li
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Yuanjun Zhu
- Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Lei He
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Bing Zheng
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
| | - Min Li
- Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, P.R. China
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25
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Zhao XC, An P, Wu XY, Zhang LM, Long B, Tian Y, Chi XY, Tong DY. Overexpression of hSNF2H in glioma promotes cell proliferation, invasion, and chemoresistance through its interaction with Rsf-1. Tumour Biol 2015; 37:7203-12. [PMID: 26666816 DOI: 10.1007/s13277-015-4579-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 12/02/2015] [Indexed: 12/30/2022] Open
Abstract
hSNF2H partners with Rsf-1 to compose the Rsf complex to regulate gene expression. Recent studies indicated that hSNF2H was overexpressed in several human cancers. However, its expression pattern and biological mechanism in glioma remain unexplored. In this study, we found that hSNF2H was overexpressed in 32 % of glioma specimens. hSNF2H overexpression correlated with advanced tumor grade (p = 0.0338) and Rsf-1 positivity in glioma tissues (p = 0.016). Small interfering RNA (siRNA) knockdown was performed in A172 and U87 cell lines. MTT, colony formation assay, and cell cycle analysis showed that knockdown of hSNF2H inhibited cell proliferation, colony formation ability, and cell cycle transition. Matrigel invasion assay showed that hSNF2H depletion inhibited invasive ability of glioma cells. In addition, we demonstrated that hSNF2H depletion decreased temozolomide resistance of A172 and U87 cell lines and increased temozolomide induced apoptosis. Furthermore, hSNF2H depletion decreased cyclin D1, cyclin E, p-Rb, MMP2, cIAP1, Bcl-2 expression, and phosphorylation of IκBα and p65, suggesting hSNF2H regulates apoptosis through NF-κB pathway. Immunoprecipitation showed that hSNF2H could interact with Rsf-1 in both cell lines. To validate the involvement of Rsf-1, we checked the change of its downstream targets in Rsf-1 depleted cells. In Rsf-1 depleted cells, changes of cyclin E, Bcl-2, and p-IκBα were not significant using hSNF2H siRNA treatment. In conclusion, our study demonstrated that hSNF2H was overexpressed in human gliomas and contributed to glioma proliferation, invasion, and chemoresistance through regulation of cyclin E and NF-κB pathway, which is dependent on its interaction with Rsf-1.
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Affiliation(s)
- Xiao-Chun Zhao
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China
| | - Ping An
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.
| | - Xiu-Ying Wu
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China.
| | - Li-Min Zhang
- Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, China
| | - Bo Long
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China
| | - Yue Tian
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China
| | - Xiao-Ying Chi
- Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dong-Yi Tong
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China
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Mello AA, Leal MF, Rey JA, Pinto GR, Lamarão LM, Montenegro RC, Alves APNN, Assumpção PP, Borges BDN, Smith MC, Burbano RR. Deregulated Expression of SRC, LYN and CKB Kinases by DNA Methylation and Its Potential Role in Gastric Cancer Invasiveness and Metastasis. PLoS One 2015; 10:e0140492. [PMID: 26460485 PMCID: PMC4604160 DOI: 10.1371/journal.pone.0140492] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 09/25/2015] [Indexed: 12/29/2022] Open
Abstract
Kinases are downstream modulators and effectors of several cellular signaling cascades and play key roles in the development of neoplastic disease. In this study, we aimed to evaluate SRC, LYN and CKB protein and mRNA expression, as well as their promoter methylation, in gastric cancer. We found elevated expression of SRC and LYN kinase mRNA and protein but decreased levels of CKB kinase, alterations that may have a role in the invasiveness and metastasis of gastric tumors. Expression of the three studied kinases was also associated with MYC oncogene expression, a possible biomarker for gastric cancer. To understand the mechanisms that regulate the expression of these genes, we evaluated the DNA promoter methylation of the three kinases. We found that reduced SRC and LYN methylation and increased CKB methylation was associated with gastric cancer. The reduced SRC and LYN methylation was associated with increased levels of mRNA and protein expression, suggesting that DNA methylation is involved in regulating the expression of these kinases. Conversely, reduced CKB methylation was observed in samples with reduced mRNA and protein expression, suggesting CKB expression was found to be only partly regulated by DNA methylation. Additionally, we found that alterations in the DNA methylation pattern of the three studied kinases were also associated with the gastric cancer onset, advanced gastric cancer, deeper tumor invasion and the presence of metastasis. Therefore, SRC, LYN and CKB expression or DNA methylation could be useful markers for predicting tumor progression and targeting in anti-cancer strategies.
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Affiliation(s)
- Adriano Azevedo Mello
- Centro de Ciências Biológicas e da Saúde, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil
| | - Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
- * E-mail:
| | - Juan Antonio Rey
- Laboratorio de Oncogenética Molecular, Hospital Universitario La Paz, Madrid, Madrid, Spain
| | | | - Leticia Martins Lamarão
- Laboratório de Testes de Ácidos Nucleicos, Fundação Centro de Hemoterapia e Hematologia do Pará, Belém, PA, Brazil
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | | | | | - Paulo Pimentel Assumpção
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
| | - Barbara do Nascimento Borges
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Centro de Tecnologia Agropecuária, Instituto Socioambiental e dos Recursos Hídricos, Universidade Federal Rural da Amazônia, Belém, PA, Brazil
| | - Marília Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Rommel Rodriguez Burbano
- Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
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27
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Cutcutache I, Suzuki Y, Tan IB, Ramgopal S, Zhang S, Ramnarayanan K, Gan A, Lee HH, Tay ST, Ooi A, Ong CK, Bolthouse JT, Lane BR, Anema JG, Kahnoski RJ, Tan P, Teh BT, Rozen SG. Exome-wide Sequencing Shows Low Mutation Rates and Identifies Novel Mutated Genes in Seminomas. Eur Urol 2015; 68:77-83. [PMID: 25597018 DOI: 10.1016/j.eururo.2014.12.040] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 12/29/2014] [Indexed: 12/23/2022]
Abstract
BACKGROUND Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors. OBJECTIVE The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations. DESIGN, SETTING, AND PARTICIPANTS Eight seminomas and matched normal samples were surgically obtained from eight patients. INTERVENTION DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality. RESULTS AND LIMITATIONS The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic. CONCLUSIONS Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy. PATIENT SUMMARY We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.
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Affiliation(s)
- Ioana Cutcutache
- Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
| | - Yuka Suzuki
- Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
| | - Iain Beehuat Tan
- Department of Medical Oncology, National Cancer Centre Singapore, Singapore; Genome Institute of Singapore, A*STAR, Singapore
| | - Subhashini Ramgopal
- Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
| | - Shenli Zhang
- Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
| | - Kalpana Ramnarayanan
- Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
| | - Anna Gan
- Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
| | - Heng Hong Lee
- Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
| | - Su Ting Tay
- Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore
| | - Aikseng Ooi
- Laboratory of Interdisciplinary Renal Oncology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Choon Kiat Ong
- Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
| | | | - Brian R Lane
- Division of Urology, Spectrum Health Hospital System, Grand Rapids, MI, USA
| | - John G Anema
- Division of Urology, Spectrum Health Hospital System, Grand Rapids, MI, USA
| | - Richard J Kahnoski
- Division of Urology, Spectrum Health Hospital System, Grand Rapids, MI, USA
| | - Patrick Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Genome Institute of Singapore, A*STAR, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
| | - Bin Tean Teh
- Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
| | - Steven G Rozen
- Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
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Overexpression of SMARCA5 correlates with cell proliferation and migration in breast cancer. Tumour Biol 2014; 36:1895-902. [PMID: 25377162 DOI: 10.1007/s13277-014-2791-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 10/29/2014] [Indexed: 12/26/2022] Open
Abstract
SMARCA5 partners with RSF-1 to compose the RSF complex, which belongs to the ISWI family of chromatin remodelers. Recent studies referred that SMARCA5 was overexpressed in some malignant tumors. However, expression pattern and biological roles of SMARCA5 in breast cancer have not been examined. In the present study, we found that SMARCA5 was overexpressed in breast cancer specimens by immunohistochemistry. Significant association was observed between SMARCA5 overexpression and TNM stage (p = 0.0199), tumor size (p = 0.0066), high proliferation index (p = 0.0366), and poor overall survival (p = 0.0141). SMARCA5 overexpression also correlated with Rsf-1 expression levels (p = 0.0120). Furthermore, colony formation assay and Matrigel invasion assay showed that knockdown of SMARCA5 expression in MDA-MB-231 and MDA-MB-435s cell lines with high endogenous expression decreased cell proliferation and cell invasion. Flow cytometry showed knockdown of SMARCA5-arrested cell cycle. Further analysis of cell cycle and invasion-related molecules showed that SMARCA5 downregulated cyclin A, MMP2 expression and upregulated p21 expression. In conclusion, our study demonstrated that SMARCA5 was overexpressed in human breast cancers and correlated with poor prognosis. SMARCA5 contributes to breast cancer cell proliferation and invasion.
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29
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Alternative lengthening of telomeres: recurrent cytogenetic aberrations and chromosome stability under extreme telomere dysfunction. Neoplasia 2014; 15:1301-13. [PMID: 24339742 DOI: 10.1593/neo.131574] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 10/17/2013] [Accepted: 10/21/2013] [Indexed: 12/23/2022] Open
Abstract
Human tumors using the alternative lengthening of telomeres (ALT) exert high rates of telomere dysfunction. Numerical chromosomal aberrations are very frequent, and structural rearrangements are widely scattered among the genome. This challenging context allows the study of telomere dysfunction-driven chromosomal instability in neoplasia (CIN) in a massive scale. We used molecular cytogenetics to achieve detailed karyotyping in 10 human ALT neoplastic cell lines. We identified 518 clonal recombinant chromosomes affected by 649 structural rearrangements. While all human chromosomes were involved in random or clonal, terminal, or pericentromeric rearrangements and were capable to undergo telomere healing at broken ends, a differential recombinatorial propensity of specific genomic regions was noted. We show that ALT cells undergo epigenetic modifications rendering polycentric chromosomes functionally monocentric, and because of increased terminal recombinogenicity, they generate clonal recombinant chromosomes with interstitial telomeric repeats. Losses of chromosomes 13, X, and 22, gains of 2, 3, 5, and 20, and translocation/deletion events involving several common chromosomal fragile sites (CFSs) were recurrent. Long-term reconstitution of telomerase activity in ALT cells reduced significantly the rates of random ongoing telomeric and pericentromeric CIN. However, the contribution of CFS in overall CIN remained unaffected, suggesting that in ALT cells whole-genome replication stress is not suppressed by telomerase activation. Our results provide novel insights into ALT-driven CIN, unveiling in parallel specific genomic sites that may harbor genes critical for ALT cancerous cell growth.
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30
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Kang C, Song JJ, Lee J, Kim MY. Epigenetics: An emerging player in gastric cancer. World J Gastroenterol 2014; 20:6433-6447. [PMID: 24914365 PMCID: PMC4047329 DOI: 10.3748/wjg.v20.i21.6433] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 01/21/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Cancers, like other diseases, arise from gene mutations and/or altered gene expression, which eventually cause dysregulation of numerous proteins and noncoding RNAs. Changes in gene expression, i.e., upregulation of oncogenes and/or downregulation of tumor suppressor genes, can be generated not only by genetic and environmental factors but also by epigenetic factors, which are inheritable but nongenetic modifications of cellular chromosome components. Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies. The search for genetic and environmental factors has a long history in cancer research, but epigenetic factors only recently began to be associated with cancer formation, progression, and metastasis. Epigenetic alterations of chromatin include DNA methylation and histone modifications, which can affect gene-expression profiles. Recent studies have revealed diverse mechanisms by which chromatin modifiers, including writers, erasers and readers of the aforementioned modifications, contribute to the formation and progression of cancer. Furthermore, functional RNAs, such as microRNAs and long noncoding RNAs, have also been identified as key players in these processes. This review highlights recent findings concerning the epigenetic alterations associated with cancers, especially gastric cancer.
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Epigenetic biomarkers: potential applications in gastrointestinal cancers. ISRN GASTROENTEROLOGY 2014; 2014:464015. [PMID: 24729878 PMCID: PMC3963109 DOI: 10.1155/2014/464015] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 01/25/2014] [Indexed: 12/14/2022]
Abstract
Genetics and epigenetics coregulate the cancer initiation and progression. Epigenetic mechanisms include DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs. Aberrant epigenetic modifications play a fundamental role in the formation of gastrointestinal cancers. Advances in epigenetics offer a better understanding of the carcinogenesis and provide new insights into the discovery of biomarkers for diagnosis, and prognosis prediction of human cancers. This review aims to overview the epigenetic aberrance and the clinical applications as biomarkers in gastrointestinal cancers mainly gastric cancer and colorectal cancer.
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Association of COX2 gene hypomethylation with intestinal type gastric cancer in samples of patients from northern Brazil. Tumour Biol 2013; 35:1107-11. [PMID: 24014049 DOI: 10.1007/s13277-013-1148-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 08/26/2013] [Indexed: 12/28/2022] Open
Abstract
To verify the methylation status of THBS1, GPX3, and COX2 genes and to evaluate their association with Helicobacter pylori in gastric adenocarcinomas. Methylation-sensitive restriction enzyme PCR assay was performed in 16 diffuse type gastric cancer samples, 23 intestinal type, and 15 normal stomach tissue. The presence of H. pylori was performed by amplification of the fragment of the 16S rRNA. Statistical analyses were performed using Fisher's exact test. The hypermethylation of GPX3, THBS1, and COX2 occurred in 18 (n = 7), 5 (n = 2), and 36 % (n = 14) of gastric cancer samples, respectively, whereas in normal samples, it was found in 13, 7, and 67 %. The presence of H. pylori was detected in 67 % of gastric cancer samples and 67 % in normal gastric samples. The methylation of THBS1 and GPX3 was not significantly different between the types of tumors, normal sample, the presence of H. pylori, or clinicopathological variables studied (P > 0.05). However, the methylation status of the gene COX2 is significantly different between normal tissue and intestinal type gastric cancer (P = 0.02). Therefore, our results suggest that the methylation status of the gene COX2 is associated with the intestinal type of gastric cancer.
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33
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Smeenk G, van Attikum H. The chromatin response to DNA breaks: leaving a mark on genome integrity. Annu Rev Biochem 2013; 82:55-80. [PMID: 23414304 DOI: 10.1146/annurev-biochem-061809-174504] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Genetic, biochemical, and cellular studies have uncovered many of the molecular mechanisms underlying the signaling and repair of chromosomal DNA breaks. However, efficient repair of DNA damage is complicated in that genomic DNA is packaged, through histone and nonhistone proteins, into chromatin. The DNA repair machinery has to overcome this physical barrier to gain access to damaged DNA and repair DNA lesions. Posttranslational modifications of chromatin as well as ATP-dependent chromatin remodeling factors help to overcome this barrier and facilitate access to damaged DNA by altering chromatin structure at sites of DNA damage. Here we review and discuss our current knowledge of and recent advances in chromatin changes induced by chromosome breakage in mammalian cells and their implications for genome stability and human disease.
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Affiliation(s)
- Godelieve Smeenk
- Department of Toxicogenetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands
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34
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Molecular detection and targeting of EWSR1 fusion transcripts in soft tissue tumors. Med Oncol 2013; 30:412. [PMID: 23329308 PMCID: PMC3586390 DOI: 10.1007/s12032-012-0412-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 11/30/2012] [Indexed: 12/11/2022]
Abstract
Soft tissue tumors are a heterogeneous group of tumors, traditionally classified according to morphology and histogenesis. Molecular classification divides sarcomas into two main categories: (a) sarcomas with specific genetic alterations and (b) sarcomas showing multiple complex karyotypic abnormalities without any specific pattern. Most chromosomal alterations are represented by translocations which are increasingly detected. The identification of fusion transcripts, in fact, not only support the diagnosis but also provides the basis for the development of new therapeutic strategies aimed at blocking aberrant activity of the chimeric proteins. One of the genes most susceptible to breakage/translocation in soft tissue tumors is represented by Ewing sarcoma breakpoint region 1 (EWSR1). This gene has a large number of fusion partners, mainly associated with the pathogenesis of Ewing's sarcoma but with other soft tissue tumors too. In this review, we illustrate the characteristics of this gene/protein, both in normal cellular physiology and in carcinogenesis. We describe the different fusion partners of EWSR1, the molecular pathways in which is involved and the main molecular biology techniques for the identification of fusion transcripts and for their inhibition.
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35
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Gigek CO, Chen ES, Calcagno DQ, Wisnieski F, Burbano RR, Smith MAC. Epigenetic mechanisms in gastric cancer. Epigenomics 2012; 4:279-94. [PMID: 22690664 DOI: 10.2217/epi.12.22] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cancer is considered one of the major health issues worldwide, and gastric cancer accounted for 8% of total cases and 10% of total deaths in 2008. Gastric cancer is considered an age-related disease, and the total number of newly diagnosed cases has been increasing as a result of the higher life expectancy. Therefore, the basic mechanisms underlying gastric tumorigenesis is worth investigation. This review provides an overview of the epigenetic mechanisms, such as DNA methylation, histone modifications, chromatin remodeling complex and miRNA, involved in gastric cancer. As the studies in gastric cancer continue, the mapping of an epigenome code is not far for this disease. In conclusion, an epigenetic therapy might appear in the not too distant future.
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Affiliation(s)
- Carolina Oliveira Gigek
- Disciplina de Genética, Departamento de Morfologia e Genética, Escola Paulista de Medicina/Universidade Federal de São Paulo, Rua Botucatu 740, São Paulo, SP, Brazil.
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Nucleosome remodeler SNF2L suppresses cell proliferation and migration and attenuates Wnt signaling. Mol Cell Biol 2012; 32:2359-71. [PMID: 22508985 DOI: 10.1128/mcb.06619-11] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
ISWI is an evolutionarily conserved ATPase that catalyzes nucleosome remodeling in different macromolecular complexes. Two mammalian ISWI orthologs, SNF2H and SNF2L, are thought to have specialized functions despite their high sequence similarity. To date, the function of SNF2L in human cells has not been a focus of research. Newly established specific monoclonal antibodies and selective RNA interference protocols have now enabled a comprehensive characterization of loss-of-function phenotypes in human cells. In contrast to earlier results, we found SNF2L to be broadly expressed in primary human tissues. Depletion of SNF2L in HeLa cells led to enhanced proliferation and increased migration. These phenomena were explained by transcriptome profiling, which identified SNF2L as a modulator of the Wnt signaling network. The cumulative effects of SNF2L depletion on gene expression portray the cell in a state of activated Wnt signaling characterized by increased proliferation and chemotactic locomotion. Accordingly, high levels of SNF2L expression in normal melanocytes contrast with undetectable expression in malignant melanoma. In summary, our data document an inverse relationship between SNF2L expression and features characteristic of malignant cells.
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