PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma
Pleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determine <i>PLEKHS1</i> promoter hotspot mutations in papillary and ana...
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MDPI AG
2020-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2133 |
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| author | Xiangling Xing Ninni Mu Xiaotian Yuan Na Wang C. Christofer Juhlin Klas Strååt Catharina Larsson Dawei Xu |
| author_facet | Xiangling Xing Ninni Mu Xiaotian Yuan Na Wang C. Christofer Juhlin Klas Strååt Catharina Larsson Dawei Xu |
| author_sort | Xiangling Xing |
| collection | DOAJ |
| description | Pleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determine <i>PLEKHS1</i> promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) and to evaluate if <i>PLEKHS1</i> expression influences clinical outcome. The <i>PLEKHS1</i> promoter mutation was observed in 1/93 of PTCs and none of 18 ATCs in our cohort; however, <i>PLEKHS1</i> expression was aberrantly up-regulated in TCs compared to adjacent non-tumorous thyroid tissues. ATC tumors, an undifferentiated TC, exhibited the highest <i>PLEKHS1</i> expression. In both TCGA and present cohorts of PTCs, <i>PLEKHS1</i> gene methylation density was inversely correlated with its mRNA expression and demethylation at the <i>PLEKHS1</i> locus occurred at two CpGs. Higher <i>PLEKHS1</i> expression was associated with lymph node and distant metastases, and shorter overall and disease-free survival in our cohort of PTC patients. Importantly, <i>PLEKHS1</i> over-expression predicted shorter patient survival in PTCs lacking <i>TERT</i> promoter mutations. Cellular experiments showed that <i>PLEKHS1</i> over-expression enhanced AKT phosphorylation and invasiveness. Collectively, the <i>PLEKHS1</i> gene demethylation causes its over-expression in PTCs. <i>PLEKHS1</i> promotes aggressive behavior of TCs possibly by increasing AKT activity, and its over-expression predicts poor patient outcomes. |
| first_indexed | 2024-03-10T18:02:59Z |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T18:02:59Z |
| publishDate | 2020-07-01 |
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| series | Cancers |
| spelling | doaj.art-3f711289660f427a87c7b6b587ef45682023-11-20T08:43:40ZengMDPI AGCancers2072-66942020-07-01128213310.3390/cancers12082133PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid CarcinomaXiangling Xing0Ninni Mu1Xiaotian Yuan2Na Wang3C. Christofer Juhlin4Klas Strååt5Catharina Larsson6Dawei Xu7Department of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, SE-171 76 Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Bioclinicum, SE-171 76 Stockholm, SwedenDepartment of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, SE-171 76 Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Bioclinicum, SE-171 76 Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Bioclinicum, SE-171 76 Stockholm, SwedenDepartment of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, SE-171 76 Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Bioclinicum, SE-171 76 Stockholm, SwedenDepartment of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, SE-171 76 Stockholm, SwedenPleckstrin homology domain containing S1 (PLEKHS1) is a poorly characterized factor, although its promoter mutations were identified in human malignancies including thyroid carcinoma (TC). This study was designed to determine <i>PLEKHS1</i> promoter hotspot mutations in papillary and anaplastic thyroid carcinomas (PTCs and ATCs) and to evaluate if <i>PLEKHS1</i> expression influences clinical outcome. The <i>PLEKHS1</i> promoter mutation was observed in 1/93 of PTCs and none of 18 ATCs in our cohort; however, <i>PLEKHS1</i> expression was aberrantly up-regulated in TCs compared to adjacent non-tumorous thyroid tissues. ATC tumors, an undifferentiated TC, exhibited the highest <i>PLEKHS1</i> expression. In both TCGA and present cohorts of PTCs, <i>PLEKHS1</i> gene methylation density was inversely correlated with its mRNA expression and demethylation at the <i>PLEKHS1</i> locus occurred at two CpGs. Higher <i>PLEKHS1</i> expression was associated with lymph node and distant metastases, and shorter overall and disease-free survival in our cohort of PTC patients. Importantly, <i>PLEKHS1</i> over-expression predicted shorter patient survival in PTCs lacking <i>TERT</i> promoter mutations. Cellular experiments showed that <i>PLEKHS1</i> over-expression enhanced AKT phosphorylation and invasiveness. Collectively, the <i>PLEKHS1</i> gene demethylation causes its over-expression in PTCs. <i>PLEKHS1</i> promotes aggressive behavior of TCs possibly by increasing AKT activity, and its over-expression predicts poor patient outcomes.https://www.mdpi.com/2072-6694/12/8/2133metastasisPLEKHS1prognostic factorspromoter mutationsTERTthyroid carcinoma |
| spellingShingle | Xiangling Xing Ninni Mu Xiaotian Yuan Na Wang C. Christofer Juhlin Klas Strååt Catharina Larsson Dawei Xu PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma Cancers metastasis PLEKHS1 prognostic factors promoter mutations TERT thyroid carcinoma |
| title | PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma |
| title_full | PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma |
| title_fullStr | PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma |
| title_full_unstemmed | PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma |
| title_short | PLEKHS1 Over-Expression is Associated with Metastases and Poor Outcomes in Papillary Thyroid Carcinoma |
| title_sort | plekhs1 over expression is associated with metastases and poor outcomes in papillary thyroid carcinoma |
| topic | metastasis PLEKHS1 prognostic factors promoter mutations TERT thyroid carcinoma |
| url | https://www.mdpi.com/2072-6694/12/8/2133 |
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