Prognostic Implications of miR-146b Expression and Its Functional Role in Papillary Thyroid Carcinoma
Context:Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with th...
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| Published in | The journal of clinical endocrinology and metabolism Vol. 98; no. 2; pp. E196 - E205 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Oxford University Press
01.02.2013
Copyright by The Endocrine Society |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0021-972X 1945-7197 1945-7197 |
| DOI | 10.1210/jc.2012-2666 |
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| Abstract | Context:Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model.Methodology:Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined.Results:Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73–8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis.Conclusions:Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC. |
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| AbstractList | Context:Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model.Methodology:Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined.Results:Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73–8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis.Conclusions:Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC. Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model. Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined. Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis. Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC. Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model.CONTEXTRecent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model.Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined.METHODOLOGYExpression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined.Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis.RESULTSMultivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis.Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC.CONCLUSIONSOur results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC. CONTEXT:Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model. METHODOLOGY:Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined. RESULTS:Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73–8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis. CONCLUSIONS:Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC. |
| Author | Liu, Rue-Tsuan Yang, Kuender D. Kang, Hong-Yo Chou, Chen-Kai Huang, Chao-Cheng Lan, Yueh-Wen Chou, Fong-Fu Lee, Ya-Fang |
| AuthorAffiliation | Division of Metabolism (C.-K.C., Y.-W.L., Y.-F.L., R.-T.L.), Department of Internal Medicine; Departments of Surgery (F.-F.C.) and Pathology (C.-C.H.), Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung Hsien, Taiwan; and Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan; and Department of Medical Research (K.D.Y.), Show Chwan Memorial Hospital in Chang Bing, Changhua, Taiwan |
| AuthorAffiliation_xml | – name: Division of Metabolism (C.-K.C., Y.-W.L., Y.-F.L., R.-T.L.), Department of Internal Medicine; Departments of Surgery (F.-F.C.) and Pathology (C.-C.H.), Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung Hsien, Taiwan; and Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan; and Department of Medical Research (K.D.Y.), Show Chwan Memorial Hospital in Chang Bing, Changhua, Taiwan |
| Author_xml | – sequence: 1 givenname: Chen-Kai surname: Chou fullname: Chou, Chen-Kai organization: 1Division of Metabolism (C.-K.C., Y.-W.L., Y.-F.L., R.-T.L.), Department of Internal Medicine – sequence: 2 givenname: Kuender D. surname: Yang fullname: Yang, Kuender D. organization: 5Department of Medical Research (K.D.Y.), Show Chwan Memorial Hospital in Chang Bing, Changhua, Taiwan – sequence: 3 givenname: Fong-Fu surname: Chou fullname: Chou, Fong-Fu organization: 2Departments of Surgery (F.-F.C.), Taiwan – sequence: 4 givenname: Chao-Cheng surname: Huang fullname: Huang, Chao-Cheng organization: 3Pathology (C.-C.H.), Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung Hsien, Taiwan – sequence: 5 givenname: Yueh-Wen surname: Lan fullname: Lan, Yueh-Wen organization: 1Division of Metabolism (C.-K.C., Y.-W.L., Y.-F.L., R.-T.L.), Department of Internal Medicine – sequence: 6 givenname: Ya-Fang surname: Lee fullname: Lee, Ya-Fang organization: 1Division of Metabolism (C.-K.C., Y.-W.L., Y.-F.L., R.-T.L.), Department of Internal Medicine – sequence: 7 givenname: Hong-Yo surname: Kang fullname: Kang, Hong-Yo email: hkang3@mail.cgu.edu.tw organization: 4Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan – sequence: 8 givenname: Rue-Tsuan surname: Liu fullname: Liu, Rue-Tsuan email: ruetsuan@ms2.hinet.net organization: 1Division of Metabolism (C.-K.C., Y.-W.L., Y.-F.L., R.-T.L.), Department of Internal Medicine |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23264400$$D View this record in MEDLINE/PubMed |
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| Snippet | Context:Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the... CONTEXT:Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the... Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the... |
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| SubjectTerms | Adult Apoptosis Apoptosis - genetics Carcinoma, Papillary - genetics Carcinoma, Papillary - metabolism Carcinoma, Papillary - pathology Cell adhesion & migration Cell Line, Tumor Cell migration Cell Movement - genetics Cell proliferation Chemotherapy Female Follow-Up Studies Gene Expression Regulation, Neoplastic Humans Invasiveness Lymph nodes Lymphatic Metastasis - genetics Lymphatic Metastasis - pathology Male Medical prognosis Medical records Metastases MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Middle Aged miRNA Molecular modelling Mutation Neoplasm Invasiveness - genetics Neoplasm Invasiveness - pathology Papillary thyroid cancer Papillary thyroid carcinoma Prognosis Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Risk factors Thyroid cancer Thyroid Neoplasms - genetics Thyroid Neoplasms - metabolism Thyroid Neoplasms - pathology Tumors |
| Title | Prognostic Implications of miR-146b Expression and Its Functional Role in Papillary Thyroid Carcinoma |
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