The microRNA expression signature of bladder cancer by deep sequencing: the functional significance of the miR-195/497 cluster
Current genome-wide microRNA (miRNA) expression signature analysis using deep sequencing technologies can drive the discovery of novel cancer pathways regulated by oncogenic and/or tumor suppressive miRNAs. We determined the genome-wide miRNA expression signature in bladder cancer (BC) by deep seque...
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| Veröffentlicht in: | PloS one 2014-02, Vol.9 (2), p.e84311-e84311 |
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| creator | Itesako, Toshihiko Seki, Naohiko Yoshino, Hirofumi Chiyomaru, Takeshi Yamasaki, Takeshi Hidaka, Hideo Yonezawa, Tomokazu Nohata, Nijiro Kinoshita, Takashi Nakagawa, Masayuki Enokida, Hideki |
| description | Current genome-wide microRNA (miRNA) expression signature analysis using deep sequencing technologies can drive the discovery of novel cancer pathways regulated by oncogenic and/or tumor suppressive miRNAs. We determined the genome-wide miRNA expression signature in bladder cancer (BC) by deep sequencing technology. A total of ten small RNA libraries were sequenced (five BCs and five samples of histologically normal bladder epithelia (NBE)), and 13,190,619 to 18,559,060 clean small RNA reads were obtained. A total of 933 known miRNAs and 17 new miRNA candidates were detected in this analysis. Among the known miRNAs, a total of 60 miRNAs were significantly downregulated in BC compared with NBE. We also found that several miRNAs, such as miR-1/133a, miR-206/133b, let-7c/miR-99a, miR-143/145 and miR-195/497, were located close together at five distinct loci and constituted clustered miRNAs. Among these clustered miRNAs, we focused on the miR-195/497 cluster because this clustered miRNA had not been analyzed in BC. Transfection of mature miR-195 or miR-497 in two BC cell lines (BOY and T24) significantly inhibited cancer cell proliferation, migration and invasion, suggesting that the miR-195/497 cluster functioned as tumor suppressors in BC. Regarding the genes targeted by the miR-195/497 cluster, the TargetScan algorithm showed that 6,730 genes were putative miR-195/497 targets, and 113 significantly enriched signaling pathways were identified in this analysis. The "Pathways in cancer" category was the most enriched, involving 104 candidate target genes. Gene expression data revealed that 27 of 104 candidate target genes were actually upregulated in BC clinical specimens. Luciferase reporter assays and Western blotting demonstrated that BIRC5 and WNT7A were directly targeted by miR-195/497. In conclusion, aberrant expression of clustered miRNAs was identified by deep sequencing, and downregulation of miR-195/497 contributed to BC progression and metastasis. Tumor suppressive miRNA-mediated cancer pathways provide new insights into the potential mechanisms of BC oncogenesis. |
| doi_str_mv | 10.1371/journal.pone.0084311 |
| format | Article |
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We determined the genome-wide miRNA expression signature in bladder cancer (BC) by deep sequencing technology. A total of ten small RNA libraries were sequenced (five BCs and five samples of histologically normal bladder epithelia (NBE)), and 13,190,619 to 18,559,060 clean small RNA reads were obtained. A total of 933 known miRNAs and 17 new miRNA candidates were detected in this analysis. Among the known miRNAs, a total of 60 miRNAs were significantly downregulated in BC compared with NBE. We also found that several miRNAs, such as miR-1/133a, miR-206/133b, let-7c/miR-99a, miR-143/145 and miR-195/497, were located close together at five distinct loci and constituted clustered miRNAs. Among these clustered miRNAs, we focused on the miR-195/497 cluster because this clustered miRNA had not been analyzed in BC. Transfection of mature miR-195 or miR-497 in two BC cell lines (BOY and T24) significantly inhibited cancer cell proliferation, migration and invasion, suggesting that the miR-195/497 cluster functioned as tumor suppressors in BC. Regarding the genes targeted by the miR-195/497 cluster, the TargetScan algorithm showed that 6,730 genes were putative miR-195/497 targets, and 113 significantly enriched signaling pathways were identified in this analysis. The "Pathways in cancer" category was the most enriched, involving 104 candidate target genes. Gene expression data revealed that 27 of 104 candidate target genes were actually upregulated in BC clinical specimens. Luciferase reporter assays and Western blotting demonstrated that BIRC5 and WNT7A were directly targeted by miR-195/497. In conclusion, aberrant expression of clustered miRNAs was identified by deep sequencing, and downregulation of miR-195/497 contributed to BC progression and metastasis. Tumor suppressive miRNA-mediated cancer pathways provide new insights into the potential mechanisms of BC oncogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0084311</identifier><identifier>PMID: 24520312</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Aged ; Aged, 80 and over ; Analysis ; Apoptosis ; Base Sequence ; Bioinformatics ; Biology ; Bladder ; Bladder cancer ; Breast cancer ; Cancer ; Cell cycle ; Cell Line, Tumor ; Cell migration ; Cell Movement ; Cell Proliferation ; Clusters ; Down-Regulation - genetics ; Epithelium - metabolism ; Epithelium - pathology ; Female ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene sequencing ; Genes ; Genomes ; Genomics ; High-Throughput Nucleotide Sequencing - methods ; Humans ; Kinases ; Male ; Medicine ; Metastases ; MicroRNA ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Middle Aged ; miRNA ; Molecular Sequence Annotation ; Molecular Sequence Data ; Neoplasm Invasiveness ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Ribonucleic acid ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Signal Transduction - genetics ; Signaling ; Signature analysis ; Studies ; Suppressors ; Transfection ; Tumorigenesis ; Tumors ; University graduates ; Urinary bladder ; Urinary Bladder - metabolism ; Urinary Bladder - pathology ; Urinary Bladder Neoplasms - genetics ; Urinary Bladder Neoplasms - pathology ; Urology ; Western blotting</subject><ispartof>PloS one, 2014-02, Vol.9 (2), p.e84311-e84311</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Itesako et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Itesako et al 2014 Itesako et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-3544ce868134bc700c311982f923ef91ffb2019fca9bba6e61a08d3f80c5c3283</citedby><cites>FETCH-LOGICAL-c758t-3544ce868134bc700c311982f923ef91ffb2019fca9bba6e61a08d3f80c5c3283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919700/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919700/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23871,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24520312$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Futscher, Bernard W.</contributor><creatorcontrib>Itesako, Toshihiko</creatorcontrib><creatorcontrib>Seki, Naohiko</creatorcontrib><creatorcontrib>Yoshino, Hirofumi</creatorcontrib><creatorcontrib>Chiyomaru, Takeshi</creatorcontrib><creatorcontrib>Yamasaki, Takeshi</creatorcontrib><creatorcontrib>Hidaka, Hideo</creatorcontrib><creatorcontrib>Yonezawa, Tomokazu</creatorcontrib><creatorcontrib>Nohata, Nijiro</creatorcontrib><creatorcontrib>Kinoshita, Takashi</creatorcontrib><creatorcontrib>Nakagawa, Masayuki</creatorcontrib><creatorcontrib>Enokida, Hideki</creatorcontrib><title>The microRNA expression signature of bladder cancer by deep sequencing: the functional significance of the miR-195/497 cluster</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Current genome-wide microRNA (miRNA) expression signature analysis using deep sequencing technologies can drive the discovery of novel cancer pathways regulated by oncogenic and/or tumor suppressive miRNAs. We determined the genome-wide miRNA expression signature in bladder cancer (BC) by deep sequencing technology. A total of ten small RNA libraries were sequenced (five BCs and five samples of histologically normal bladder epithelia (NBE)), and 13,190,619 to 18,559,060 clean small RNA reads were obtained. A total of 933 known miRNAs and 17 new miRNA candidates were detected in this analysis. Among the known miRNAs, a total of 60 miRNAs were significantly downregulated in BC compared with NBE. We also found that several miRNAs, such as miR-1/133a, miR-206/133b, let-7c/miR-99a, miR-143/145 and miR-195/497, were located close together at five distinct loci and constituted clustered miRNAs. Among these clustered miRNAs, we focused on the miR-195/497 cluster because this clustered miRNA had not been analyzed in BC. Transfection of mature miR-195 or miR-497 in two BC cell lines (BOY and T24) significantly inhibited cancer cell proliferation, migration and invasion, suggesting that the miR-195/497 cluster functioned as tumor suppressors in BC. Regarding the genes targeted by the miR-195/497 cluster, the TargetScan algorithm showed that 6,730 genes were putative miR-195/497 targets, and 113 significantly enriched signaling pathways were identified in this analysis. The "Pathways in cancer" category was the most enriched, involving 104 candidate target genes. Gene expression data revealed that 27 of 104 candidate target genes were actually upregulated in BC clinical specimens. Luciferase reporter assays and Western blotting demonstrated that BIRC5 and WNT7A were directly targeted by miR-195/497. In conclusion, aberrant expression of clustered miRNAs was identified by deep sequencing, and downregulation of miR-195/497 contributed to BC progression and metastasis. Tumor suppressive miRNA-mediated cancer pathways provide new insights into the potential mechanisms of BC oncogenesis.</description><subject>Aberration</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Base Sequence</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Bladder</subject><subject>Bladder cancer</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Clusters</subject><subject>Down-Regulation - genetics</subject><subject>Epithelium - metabolism</subject><subject>Epithelium - pathology</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Genomes</subject><subject>Genomics</subject><subject>High-Throughput Nucleotide Sequencing - methods</subject><subject>Humans</subject><subject>Kinases</subject><subject>Male</subject><subject>Medicine</subject><subject>Metastases</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>Middle Aged</subject><subject>miRNA</subject><subject>Molecular Sequence Annotation</subject><subject>Molecular Sequence Data</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction - genetics</subject><subject>Signaling</subject><subject>Signature analysis</subject><subject>Studies</subject><subject>Suppressors</subject><subject>Transfection</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>University graduates</subject><subject>Urinary bladder</subject><subject>Urinary Bladder - 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genetics</topic><topic>Epithelium - metabolism</topic><topic>Epithelium - pathology</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene sequencing</topic><topic>Genes</topic><topic>Genomes</topic><topic>Genomics</topic><topic>High-Throughput Nucleotide Sequencing - methods</topic><topic>Humans</topic><topic>Kinases</topic><topic>Male</topic><topic>Medicine</topic><topic>Metastases</topic><topic>MicroRNA</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>Middle Aged</topic><topic>miRNA</topic><topic>Molecular Sequence Annotation</topic><topic>Molecular Sequence Data</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction - genetics</topic><topic>Signaling</topic><topic>Signature analysis</topic><topic>Studies</topic><topic>Suppressors</topic><topic>Transfection</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><topic>University graduates</topic><topic>Urinary bladder</topic><topic>Urinary Bladder - metabolism</topic><topic>Urinary Bladder - pathology</topic><topic>Urinary Bladder Neoplasms - genetics</topic><topic>Urinary Bladder Neoplasms - pathology</topic><topic>Urology</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Itesako, Toshihiko</creatorcontrib><creatorcontrib>Seki, Naohiko</creatorcontrib><creatorcontrib>Yoshino, Hirofumi</creatorcontrib><creatorcontrib>Chiyomaru, Takeshi</creatorcontrib><creatorcontrib>Yamasaki, Takeshi</creatorcontrib><creatorcontrib>Hidaka, Hideo</creatorcontrib><creatorcontrib>Yonezawa, Tomokazu</creatorcontrib><creatorcontrib>Nohata, Nijiro</creatorcontrib><creatorcontrib>Kinoshita, Takashi</creatorcontrib><creatorcontrib>Nakagawa, Masayuki</creatorcontrib><creatorcontrib>Enokida, Hideki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Itesako, Toshihiko</au><au>Seki, Naohiko</au><au>Yoshino, Hirofumi</au><au>Chiyomaru, Takeshi</au><au>Yamasaki, Takeshi</au><au>Hidaka, Hideo</au><au>Yonezawa, Tomokazu</au><au>Nohata, Nijiro</au><au>Kinoshita, Takashi</au><au>Nakagawa, Masayuki</au><au>Enokida, Hideki</au><au>Futscher, Bernard W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The microRNA expression signature of bladder cancer by deep sequencing: the functional significance of the miR-195/497 cluster</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-02-10</date><risdate>2014</risdate><volume>9</volume><issue>2</issue><spage>e84311</spage><epage>e84311</epage><pages>e84311-e84311</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Current genome-wide microRNA (miRNA) expression signature analysis using deep sequencing technologies can drive the discovery of novel cancer pathways regulated by oncogenic and/or tumor suppressive miRNAs. We determined the genome-wide miRNA expression signature in bladder cancer (BC) by deep sequencing technology. A total of ten small RNA libraries were sequenced (five BCs and five samples of histologically normal bladder epithelia (NBE)), and 13,190,619 to 18,559,060 clean small RNA reads were obtained. A total of 933 known miRNAs and 17 new miRNA candidates were detected in this analysis. Among the known miRNAs, a total of 60 miRNAs were significantly downregulated in BC compared with NBE. We also found that several miRNAs, such as miR-1/133a, miR-206/133b, let-7c/miR-99a, miR-143/145 and miR-195/497, were located close together at five distinct loci and constituted clustered miRNAs. Among these clustered miRNAs, we focused on the miR-195/497 cluster because this clustered miRNA had not been analyzed in BC. Transfection of mature miR-195 or miR-497 in two BC cell lines (BOY and T24) significantly inhibited cancer cell proliferation, migration and invasion, suggesting that the miR-195/497 cluster functioned as tumor suppressors in BC. Regarding the genes targeted by the miR-195/497 cluster, the TargetScan algorithm showed that 6,730 genes were putative miR-195/497 targets, and 113 significantly enriched signaling pathways were identified in this analysis. The "Pathways in cancer" category was the most enriched, involving 104 candidate target genes. Gene expression data revealed that 27 of 104 candidate target genes were actually upregulated in BC clinical specimens. Luciferase reporter assays and Western blotting demonstrated that BIRC5 and WNT7A were directly targeted by miR-195/497. In conclusion, aberrant expression of clustered miRNAs was identified by deep sequencing, and downregulation of miR-195/497 contributed to BC progression and metastasis. Tumor suppressive miRNA-mediated cancer pathways provide new insights into the potential mechanisms of BC oncogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24520312</pmid><doi>10.1371/journal.pone.0084311</doi><tpages>e84311</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-02, Vol.9 (2), p.e84311-e84311 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1497948246 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Aberration Aged Aged, 80 and over Analysis Apoptosis Base Sequence Bioinformatics Biology Bladder Bladder cancer Breast cancer Cancer Cell cycle Cell Line, Tumor Cell migration Cell Movement Cell Proliferation Clusters Down-Regulation - genetics Epithelium - metabolism Epithelium - pathology Female Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene sequencing Genes Genomes Genomics High-Throughput Nucleotide Sequencing - methods Humans Kinases Male Medicine Metastases MicroRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Middle Aged miRNA Molecular Sequence Annotation Molecular Sequence Data Neoplasm Invasiveness Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Ribonucleic acid RNA RNA, Messenger - genetics RNA, Messenger - metabolism Signal Transduction - genetics Signaling Signature analysis Studies Suppressors Transfection Tumorigenesis Tumors University graduates Urinary bladder Urinary Bladder - metabolism Urinary Bladder - pathology Urinary Bladder Neoplasms - genetics Urinary Bladder Neoplasms - pathology Urology Western blotting |
| title | The microRNA expression signature of bladder cancer by deep sequencing: the functional significance of the miR-195/497 cluster |
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