Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation

Yi Ming Cao, Jun Gu, Yan Shu Zhang, Wen Jun Wei, Ning Qu, Duo Wen, Tian Liao, Rong Liang Shi, Ling Zhang, Qing Hai Ji, Yu Wang, Guo Hua Sun, Yang Xing Zhao, Yuan Jin Wang, Jian Yu, Yong Xue Zhu

Research output: Contribution to journalArticle

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Abstract

Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP). BRAFV600E mutation status was analyzed by polymerase chain reaction (PCR) followed by DNA sequencing. HOXD10 mRNA expression level was analyzed by real-Time polymerase chain reaction (RT-PCR). 5-Aza-2-deoxycytidine (5-Aza) treatment was performed in 4 PTC cell lines to observe the change in HOXD10 expression. Transwell, cell cycle and apoptosis assays were then performed in an HOXD10-overexpressing PTC cell line. Furthermore, we analyzed the associations between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics in PTC. Overexpression of HOXD10 suppressed the migration of PTC cells, and promoted cell apoptosis. Q-MSP showed that methylation levels of the HOXD10 promoter were significantly higher in PTC tissues than levels in the adjacent normal thyroid tissues (P=0.02). In addition, expression of HOXD10 was decreased in the PTC cell lines and PTC tissues compared with that noted in the adjacent normal thyroid tissues (P=0.008). However, BRAFV600E mutation was detected in 42.1% of PTC patients enrolled. In addition, the BRAF mutation status was associated with the methylation and expression level of HOXD10 in PTC. We then observed that 5-Aza treatment could revert the expression of HOXD10 in PTC cell lines. Moreover, the hypermethylation of HOXD10 was associated with invasion of the primary tumor and age >45. In conclusion, the HOXD10 gene may act as a tumor suppressor in PTC. The aberrant hypermethylation and decreased expression of the HOXD10 gene were shown in PTC patients, particularly in those with BRAFV600E mutation. The epigenetic suppression of the HOXD10 gene may play a role in the tumorigenesis of PTC, and it is a prospective biomarker for the diagnosis and prognosis of PTC.

Original languageEnglish (US)
Pages (from-to)338-348
Number of pages11
JournalOncology reports
Volume39
Issue number1
DOIs
StatePublished - Jan 2018

Fingerprint

Mutation
Genes
Methylation
Papillary Thyroid cancer
Cell Line
decitabine
Epigenomics
Polymerase Chain Reaction
Thyroid Gland
Carcinogenesis
Apoptosis
DNA Sequence Analysis
Real-Time Polymerase Chain Reaction
Neoplasms
Cell Cycle
Biomarkers
Gene Expression
Messenger RNA

Keywords

  • BRAF mutation
  • HOXD10
  • Methylation
  • Papillary thyroid cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cao, Y. M., Gu, J., Zhang, Y. S., Wei, W. J., Qu, N., Wen, D., ... Zhu, Y. X. (2018). Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation. Oncology reports, 39(1), 338-348. https://doi.org/10.3892/or.2017.6058

Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation. / Cao, Yi Ming; Gu, Jun; Zhang, Yan Shu; Wei, Wen Jun; Qu, Ning; Wen, Duo; Liao, Tian; Shi, Rong Liang; Zhang, Ling; Ji, Qing Hai; Wang, Yu; Sun, Guo Hua; Zhao, Yang Xing; Wang, Yuan Jin; Yu, Jian; Zhu, Yong Xue.

In: Oncology reports, Vol. 39, No. 1, 01.2018, p. 338-348.

Research output: Contribution to journalArticle

Cao, YM, Gu, J, Zhang, YS, Wei, WJ, Qu, N, Wen, D, Liao, T, Shi, RL, Zhang, L, Ji, QH, Wang, Y, Sun, GH, Zhao, YX, Wang, YJ, Yu, J & Zhu, YX 2018, 'Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation', Oncology reports, vol. 39, no. 1, pp. 338-348. https://doi.org/10.3892/or.2017.6058
Cao, Yi Ming ; Gu, Jun ; Zhang, Yan Shu ; Wei, Wen Jun ; Qu, Ning ; Wen, Duo ; Liao, Tian ; Shi, Rong Liang ; Zhang, Ling ; Ji, Qing Hai ; Wang, Yu ; Sun, Guo Hua ; Zhao, Yang Xing ; Wang, Yuan Jin ; Yu, Jian ; Zhu, Yong Xue. / Aberrant hypermethylation of the HOXD10 gene in papillary thyroid cancer with BRAFV600E mutation. In: Oncology reports. 2018 ; Vol. 39, No. 1. pp. 338-348.
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abstract = "Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP). BRAFV600E mutation status was analyzed by polymerase chain reaction (PCR) followed by DNA sequencing. HOXD10 mRNA expression level was analyzed by real-Time polymerase chain reaction (RT-PCR). 5-Aza-2-deoxycytidine (5-Aza) treatment was performed in 4 PTC cell lines to observe the change in HOXD10 expression. Transwell, cell cycle and apoptosis assays were then performed in an HOXD10-overexpressing PTC cell line. Furthermore, we analyzed the associations between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics in PTC. Overexpression of HOXD10 suppressed the migration of PTC cells, and promoted cell apoptosis. Q-MSP showed that methylation levels of the HOXD10 promoter were significantly higher in PTC tissues than levels in the adjacent normal thyroid tissues (P=0.02). In addition, expression of HOXD10 was decreased in the PTC cell lines and PTC tissues compared with that noted in the adjacent normal thyroid tissues (P=0.008). However, BRAFV600E mutation was detected in 42.1{\%} of PTC patients enrolled. In addition, the BRAF mutation status was associated with the methylation and expression level of HOXD10 in PTC. We then observed that 5-Aza treatment could revert the expression of HOXD10 in PTC cell lines. Moreover, the hypermethylation of HOXD10 was associated with invasion of the primary tumor and age >45. In conclusion, the HOXD10 gene may act as a tumor suppressor in PTC. The aberrant hypermethylation and decreased expression of the HOXD10 gene were shown in PTC patients, particularly in those with BRAFV600E mutation. The epigenetic suppression of the HOXD10 gene may play a role in the tumorigenesis of PTC, and it is a prospective biomarker for the diagnosis and prognosis of PTC.",
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