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      HOPX homeobox methylation in differentiated thyroid cancer and its clinical relevance


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          The inactivation of the tumor-suppressor homeodomain-only protein X (HOPX) usually involves promoter methylation in several cancer types. This study aimed to investigate the HOPX-β mRNA expression and promoter methylation and their clinical relevance in differentiated thyroid cancer (DTC).

          Patients and methods

          Clinicopathological data and paraffin-embedded thyroid tumor tissues from 21 patients with DTC and 6 with benign tumors (T) and their non-tumor parenchyma (NT) were investigated. Tumor cell lines (FTC238, FTC236 and WRO) were treated with demethylating agent. HOPX-β mRNA expression was assessed by qRT-PCR and methylation status by Q-MSP. Thyroid cancer data from Cancer Genome Atlas (TCGA) was also collected.


          HOPX-β mRNA re-expression in two cell lines treated with demethylating agent was observed concomitantly with reduced promoter methylation. Reduced mRNA expression in T group compared to their NT was observed, and reduced protein expression in T compared to NT was observed in three cases. Low mRNA expression with high methylation status was detected in 6/14 DTC samples. High methylation status was associated with older age at diagnosis, recurrent or progressive disease and with the presence of new neoplasm event post initial therapy while hyper-methylation correlated with worse overall survival, worse disease-free status and older age.


          A moderate coupling of downregulation of HOPX-β mRNA expression in DTC followed by high HOPX-β promoter methylation was observed however; high HOPX promoter methylation status was associated with the worse prognosis of DTC patients.

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          Most cited references26

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          The increasing incidence of thyroid cancer: the influence of access to care.

          The rapidly rising incidence of papillary thyroid cancer may be due to overdiagnosis of a reservoir of subclinical disease. To conclude that overdiagnosis is occurring, evidence for an association between access to health care and the incidence of cancer is necessary. We used Surveillance, Epidemiology, and End Results (SEER) data to examine U.S. papillary thyroid cancer incidence trends in Medicare-age and non-Medicare-age cohorts over three decades. We performed an ecologic analysis across 497 U.S. counties, examining the association of nine county-level socioeconomic markers of health care access and the incidence of papillary thyroid cancer. Papillary thyroid cancer incidence is rising most rapidly in Americans over age 65 years (annual percentage change, 8.8%), who have broad health insurance coverage through Medicare. Among those under 65, in whom health insurance coverage is not universal, the rate of increase has been slower (annual percentage change, 6.4%). Over three decades, the mortality rate from thyroid cancer has not changed. Across U.S. counties, incidence ranged widely, from 0 to 29.7 per 100,000. County papillary thyroid cancer incidence was significantly correlated with all nine sociodemographic markers of health care access: it was positively correlated with rates of college education, white-collar employment, and family income; and negatively correlated with the percentage of residents who were uninsured, in poverty, unemployed, of nonwhite ethnicity, non-English speaking, and lacking high school education. Markers for higher levels of health care access, both sociodemographic and age-based, are associated with higher papillary thyroid cancer incidence rates. More papillary thyroid cancers are diagnosed among populations with wider access to healthcare. Despite the threefold increase in incidence over three decades, the mortality rate remains unchanged. Together with the large subclinical reservoir of occult papillary thyroid cancers, these data provide supportive evidence for the widespread overdiagnosis of this entity.
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            Regulation of Raf-Akt Cross-talk.

            We have recently shown that the Ras-Raf-MEK-ERK and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathways can cross-talk in the human breast cancer cell line MCF-7. High Raf activity induces growth arrest and differentiation in these cells, whereas high PI3K/Akt activity correlates with cell survival and proliferation. Here we show that the Raf-Akt cross-talk is regulated in a concentration- and ligand-dependent manner. High doses of insulin-like growth factor I (IGF-I) activate Akt quickly and strongly enough to suppress Raf kinase activity via phosphorylation of Ser-259, whereas low doses of IGF-I do not trigger this cross-talk but are still mitogenic. Phorbol 12-myristate 13-acetate, a differentiation-inducing stimulus, potently activates the Ras-Raf-MEK-ERK pathway but only weakly activates PI3K/Akt and does not trigger the cross-talk. Thus, the herein analyzed parameters such as ligand type, concentration, and time course may contribute to the cellular response of either proliferation or differentiation. This is highly relevant to understanding cellular transformation and may be of use in areas like tissue engineering.
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              Control of alveolar differentiation by the lineage transcription factors GATA6 and HOPX inhibits lung adenocarcinoma metastasis.

              Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype. Copyright © 2013 Elsevier Inc. All rights reserved.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                December 2018
                24 October 2018
                : 7
                : 12
                : 1333-1342
                [1 ]Biological Science Department , Thyroid Molecular Sciences Laboratory, Universidade Federal de São Paulo, São Paulo, Brazil
                [2 ]Structural and Functional Biology Program , Universidade Federal de São Paulo, São Paulo, Brazil
                [3 ]Department of Bio-regulation , Thyroid Study Laboratory, Health & Science Institute, Federal University of Bahia, Salvador, Brazil
                [4 ]Post-graduate Program in Interactive Processes of Organs and Systems , Health & Science Institute, Federal University of Bahia, Salvador, Brazil
                [5 ]Department of Pathology , Sao Rafael Hospital, Salvador, Brazil
                [6 ]Department of Anatomic Pathology & Legal Medicine , Bahia Federal Medical School, Federal University of Bahia, Salvador, Brazil
                [7 ]Nuclear Medicine Department , Sao Rafael Hospital, Salvador, Brazil
                [8 ]Head and Neck Surgery Department , Sao Rafael Hospital, Salvador, Brazil
                [9 ]Division of Genetics , Department of Morphology and Genetics, Genetic Basis of Thyroid Tumors Laboratory, Paulista School of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
                Author notes
                Correspondence should be addressed to H E Ramos: ramoshelton@ 123456gmail.com

                *(E U Lima and I G S Rubio contributed equally to this work)

                © 2018 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                : 11 October 2018
                : 24 October 2018

                hopx,methylation,differentiated thyroid cancer,epigenetic


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