Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways
Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-...
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| Veröffentlicht in: | PloS one 2021-11, Vol.16 (11), p.e0260327-e0260327 |
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| creator | Amirfallah, Arsalan Knutsdottir, Hildur Arason, Adalgeir Hilmarsdottir, Bylgja Johannsson, Oskar T Agnarsson, Bjarni A Barkardottir, Rosa B Reynisdottir, Inga |
| description | Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13-1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker. |
| doi_str_mv | 10.1371/journal.pone.0260327 |
| format | Article |
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MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13-1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0260327</identifier><identifier>PMID: 34797887</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Archives & records ; Binding sites ; Biology and Life Sciences ; Biomarkers ; Biomarkers, Tumor - genetics ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cancer Survivors ; Cell Proliferation - genetics ; Cohort Studies ; Down-Regulation - genetics ; Epithelial-Mesenchymal Transition - genetics ; ErbB-2 protein ; Female ; Gene expression ; Gene Expression - genetics ; Genes ; Genetic aspects ; Genomes ; GTPase-Activating Proteins - genetics ; Humans ; Lymph nodes ; Lymph Nodes - pathology ; Medical prognosis ; Medicine ; Medicine and Health Sciences ; Mesenchyme ; MicroRNA ; MicroRNAs - genetics ; miRNA ; mRNA ; Pathology ; Pathways ; Patients ; Physical Sciences ; Prostate cancer ; Research and Analysis Methods ; Signal Transduction - genetics ; Survival ; Target recognition ; Tumor suppressor genes ; Tumor Suppressor Proteins - genetics ; Tumors</subject><ispartof>PloS one, 2021-11, Vol.16 (11), p.e0260327-e0260327</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Amirfallah 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>2021 Amirfallah et al 2021 Amirfallah et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-890e4ee58958f6b00e1c494fe19af39801eaf95a99ef18a3b0fde5d16bae041e3</citedby><cites>FETCH-LOGICAL-c692t-890e4ee58958f6b00e1c494fe19af39801eaf95a99ef18a3b0fde5d16bae041e3</cites><orcidid>0000-0002-9730-7476</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604322/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604322/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34797887$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kabekkodu, Shama Prasada</contributor><creatorcontrib>Amirfallah, Arsalan</creatorcontrib><creatorcontrib>Knutsdottir, Hildur</creatorcontrib><creatorcontrib>Arason, Adalgeir</creatorcontrib><creatorcontrib>Hilmarsdottir, Bylgja</creatorcontrib><creatorcontrib>Johannsson, Oskar T</creatorcontrib><creatorcontrib>Agnarsson, Bjarni A</creatorcontrib><creatorcontrib>Barkardottir, Rosa B</creatorcontrib><creatorcontrib>Reynisdottir, Inga</creatorcontrib><title>Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13-1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker.</description><subject>Analysis</subject><subject>Archives & records</subject><subject>Binding sites</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer Survivors</subject><subject>Cell Proliferation - genetics</subject><subject>Cohort Studies</subject><subject>Down-Regulation - genetics</subject><subject>Epithelial-Mesenchymal Transition - genetics</subject><subject>ErbB-2 protein</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression - genetics</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>GTPase-Activating Proteins - genetics</subject><subject>Humans</subject><subject>Lymph nodes</subject><subject>Lymph Nodes - pathology</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchyme</subject><subject>MicroRNA</subject><subject>MicroRNAs - 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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>Amirfallah, Arsalan</au><au>Knutsdottir, Hildur</au><au>Arason, Adalgeir</au><au>Hilmarsdottir, Bylgja</au><au>Johannsson, Oskar T</au><au>Agnarsson, Bjarni A</au><au>Barkardottir, Rosa B</au><au>Reynisdottir, Inga</au><au>Kabekkodu, Shama Prasada</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2021-11-19</date><risdate>2021</risdate><volume>16</volume><issue>11</issue><spage>e0260327</spage><epage>e0260327</epage><pages>e0260327-e0260327</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13-1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34797887</pmid><doi>10.1371/journal.pone.0260327</doi><tpages>e0260327</tpages><orcidid>https://orcid.org/0000-0002-9730-7476</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-11, Vol.16 (11), p.e0260327-e0260327 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2599573671 |
| source | Open Access: PubMed Central; MEDLINE; Public Library of Science（OA）; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Analysis Archives & records Binding sites Biology and Life Sciences Biomarkers Biomarkers, Tumor - genetics Breast cancer Breast Neoplasms - genetics Breast Neoplasms - pathology Cancer Survivors Cell Proliferation - genetics Cohort Studies Down-Regulation - genetics Epithelial-Mesenchymal Transition - genetics ErbB-2 protein Female Gene expression Gene Expression - genetics Genes Genetic aspects Genomes GTPase-Activating Proteins - genetics Humans Lymph nodes Lymph Nodes - pathology Medical prognosis Medicine Medicine and Health Sciences Mesenchyme MicroRNA MicroRNAs - genetics miRNA mRNA Pathology Pathways Patients Physical Sciences Prostate cancer Research and Analysis Methods Signal Transduction - genetics Survival Target recognition Tumor suppressor genes Tumor Suppressor Proteins - genetics Tumors |
| title | Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways |
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