Association of the promoter methylation and protein expression of Fragile Histidine Triad (FHIT) gene with the progression of differentiated thyroid carcinoma
De-Tao Yin, Lin Wang, Jianrui Sun, Fengyan Yin, Qingtao Yan, Rulong Shen, Gang He, Jian-Xin Gao, De-Tao Yin, Lin Wang, Jianrui Sun, Fengyan Yin, Qingtao Yan, Rulong Shen, Gang He, Jian-Xin Gao
Abstract
The role of aberrant methylation of fragile histidine triad (FHIT) promoters in the differentiated thyroid carcinoma (DTC) is not yet clear. Therefore, we investigated the association of the status of FHIT promoter methylation and FHIT protein expression with the clinicopathological progression of DTC, using PCR-based methylation assay and immunohistochemical technique. While no FHIT gene promoter methylation was observed in the matched non-cancerous epithelium (NCE) specimens, 24.6% of DTC samples demonstrated methylation in the FHIT promoter region. The protein expression of FHIT in NCE and DTC was 100.0% and 41.5% (P<0.01), respectively. There was a negative correlation between promoter methylation and protein expression of FHIT gene (P<0.05). Additionally, the methylation status appeared to be significantly associated with the pathological grade, tumor TNM stage, and lymph node metastasis (P<0.05), and FHIT proteins were weakly expressed in only about 20% of DTC with grade II pathological changes, TNM stage III/IV, or lymph node metastasis. Finally, the gender and tumor classification but not age marginally affected the promoter methylation and protein expression of FHIT. Our results suggest that methylation of the promoter region may play a key role in inactivation of FHIT - possibly leading to subsequent carcinogenesis and progression of DTC.
Keywords: Fragile histidine triad; carcinogenesis; differentiated thyroid carcinoma; methylation; tumor progression.
Figures
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![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2897109/bin/ijcep0003-0482-f3.jpg)
Figure 4
Association of FHIT gene promoter…
Figure 4
Association of FHIT gene promoter methylation and its protein expression with pathological and…
Figure 5
Association of FHIT gene promoter…
Figure 5
Association of FHIT gene promoter methylation and its protein expression with gender, age…
- Homozygous deletion but not mutation of exons 5 and 8 of the fragile histidine triad (FHIT) gene is associated with features of differentiated thyroid carcinoma.Yin DT, Wang L, Sun J, Yin F, Yan Q, Shen RL, Gao JX, He G. Yin DT, et al. Ann Clin Lab Sci. 2010 Summer;40(3):267-72. Ann Clin Lab Sci. 2010. PMID: 20689140
- [Methylation of promoter and expression of FHIT gene in laryngeal squamous cell carcinoma].Yin D, Dong M. Yin D, et al. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005 Mar;19(6):253-5, 258. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005. PMID: 16013507 Chinese.
- Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.Verri C, Roz L, Conte D, Liloglou T, Livio A, Vesin A, Fabbri A, Andriani F, Brambilla C, Tavecchio L, Calarco G, Calabrò E, Mancini A, Tosi D, Bossi P, Field JK, Brambilla E, Sozzi G; EUELC Consortium. Verri C, et al. Am J Respir Crit Care Med. 2009 Mar 1;179(5):396-401. doi: 10.1164/rccm.200807-1153OC. Epub 2008 Dec 18. Am J Respir Crit Care Med. 2009. PMID: 19096006
- Loss of fragile histidine triad gene expression in advanced lung cancer is consequent to allelic loss at 3p14 locus and promoter methylation.Wali A, Srinivasan R, Shabnam MS, Majumdar S, Joshi K, Behera D. Wali A, et al. Mol Cancer Res. 2006 Feb;4(2):93-9. doi: 10.1158/1541-7786.MCR-05-0070. Mol Cancer Res. 2006. PMID: 16513840
- The clinicopathological significance and drug target potential of FHIT in breast cancer, a meta-analysis and literature review.Su Y, Wang X, Li J, Xu J, Xu L. Su Y, et al. Drug Des Devel Ther. 2015 Oct 1;9:5439-45. doi: 10.2147/DDDT.S89861. eCollection 2015. Drug Des Devel Ther. 2015. PMID: 26491255 Free PMC article. Review.
- FHIT down-regulation was inversely linked to aggressive behaviors and adverse prognosis of gastric cancer: a meta- and bioinformatics analysis.Zheng HC, Liu LL. Zheng HC, et al. Oncotarget. 2017 Nov 3;8(64):108261-108273. doi: 10.18632/oncotarget.22369. eCollection 2017 Dec 8. Oncotarget. 2017. PMID: 29296239 Free PMC article.
- FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia.Bahari G, Hashemi M, Naderi M, Sadeghi-Bojd S, Taheri M. Bahari G, et al. Oncol Lett. 2017 Oct;14(4):5034-5038. doi: 10.3892/ol.2017.6796. Epub 2017 Aug 23. Oncol Lett. 2017. PMID: 29085517 Free PMC article.
- Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.Son HY, Hwangbo Y, Yoo SK, Im SW, Yang SD, Kwak SJ, Park MS, Kwak SH, Cho SW, Ryu JS, Kim J, Jung YS, Kim TH, Kim SJ, Lee KE, Park DJ, Cho NH, Sung J, Seo JS, Lee EK, Park YJ, Kim JI. Son HY, et al. Nat Commun. 2017 Jul 13;8:15966. doi: 10.1038/ncomms15966. Nat Commun. 2017. PMID: 28703219 Free PMC article.
- The clinicopathological significance and ethnic difference of FHIT hypermethylation in non-small-cell lung carcinoma: a meta-analysis and literature review.Wu X, Wu G, Yao X, Hou G, Jiang F. Wu X, et al. Drug Des Devel Ther. 2016 Feb 15;10:699-709. doi: 10.2147/DDDT.S85253. eCollection 2016. Drug Des Devel Ther. 2016. PMID: 26929601 Free PMC article. Review.
- The clinicopathological significance of FHIT hypermethylation in non-small cell lung cancer, a meta-analysis and literature review.Yan W, Xu N, Han X, Zhou XM, He B. Yan W, et al. Sci Rep. 2016 Jan 22;6:19303. doi: 10.1038/srep19303. Sci Rep. 2016. PMID: 26796853 Free PMC article. Review.
- Research Support, Non-U.S. Gov't
- Acid Anhydride Hydrolases / biosynthesis*
- Acid Anhydride Hydrolases / genetics
- Adenocarcinoma / genetics*
- Adenocarcinoma / pathology
- Adolescent
- Adult
- Aged
- DNA Methylation / genetics*
- Disease Progression
- Female
- Gene Expression
- Gene Expression Regulation, Neoplastic*
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Neoplasm Proteins / biosynthesis*
- Neoplasm Proteins / genetics
- Neoplasm Staging
- Polymerase Chain Reaction
- Promoter Regions, Genetic / genetics*
- Thyroid Neoplasms / genetics*
- Thyroid Neoplasms / pathology
- Young Adult
- Neoplasm Proteins
- fragile histidine triad protein
- Acid Anhydride Hydrolases
- Full Text Sources
- Medical
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![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2897109/bin/ijcep0003-0482-f4.jpg)
Figure 5
Association of FHIT gene promoter…
Figure 5
Association of FHIT gene promoter methylation and its protein expression with gender, age…
- Homozygous deletion but not mutation of exons 5 and 8 of the fragile histidine triad (FHIT) gene is associated with features of differentiated thyroid carcinoma.Yin DT, Wang L, Sun J, Yin F, Yan Q, Shen RL, Gao JX, He G. Yin DT, et al. Ann Clin Lab Sci. 2010 Summer;40(3):267-72. Ann Clin Lab Sci. 2010. PMID: 20689140
- [Methylation of promoter and expression of FHIT gene in laryngeal squamous cell carcinoma].Yin D, Dong M. Yin D, et al. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005 Mar;19(6):253-5, 258. Lin Chuang Er Bi Yan Hou Ke Za Zhi. 2005. PMID: 16013507 Chinese.
- Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.Verri C, Roz L, Conte D, Liloglou T, Livio A, Vesin A, Fabbri A, Andriani F, Brambilla C, Tavecchio L, Calarco G, Calabrò E, Mancini A, Tosi D, Bossi P, Field JK, Brambilla E, Sozzi G; EUELC Consortium. Verri C, et al. Am J Respir Crit Care Med. 2009 Mar 1;179(5):396-401. doi: 10.1164/rccm.200807-1153OC. Epub 2008 Dec 18. Am J Respir Crit Care Med. 2009. PMID: 19096006
- Loss of fragile histidine triad gene expression in advanced lung cancer is consequent to allelic loss at 3p14 locus and promoter methylation.Wali A, Srinivasan R, Shabnam MS, Majumdar S, Joshi K, Behera D. Wali A, et al. Mol Cancer Res. 2006 Feb;4(2):93-9. doi: 10.1158/1541-7786.MCR-05-0070. Mol Cancer Res. 2006. PMID: 16513840
- The clinicopathological significance and drug target potential of FHIT in breast cancer, a meta-analysis and literature review.Su Y, Wang X, Li J, Xu J, Xu L. Su Y, et al. Drug Des Devel Ther. 2015 Oct 1;9:5439-45. doi: 10.2147/DDDT.S89861. eCollection 2015. Drug Des Devel Ther. 2015. PMID: 26491255 Free PMC article. Review.
- FHIT down-regulation was inversely linked to aggressive behaviors and adverse prognosis of gastric cancer: a meta- and bioinformatics analysis.Zheng HC, Liu LL. Zheng HC, et al. Oncotarget. 2017 Nov 3;8(64):108261-108273. doi: 10.18632/oncotarget.22369. eCollection 2017 Dec 8. Oncotarget. 2017. PMID: 29296239 Free PMC article.
- FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia.Bahari G, Hashemi M, Naderi M, Sadeghi-Bojd S, Taheri M. Bahari G, et al. Oncol Lett. 2017 Oct;14(4):5034-5038. doi: 10.3892/ol.2017.6796. Epub 2017 Aug 23. Oncol Lett. 2017. PMID: 29085517 Free PMC article.
- Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.Son HY, Hwangbo Y, Yoo SK, Im SW, Yang SD, Kwak SJ, Park MS, Kwak SH, Cho SW, Ryu JS, Kim J, Jung YS, Kim TH, Kim SJ, Lee KE, Park DJ, Cho NH, Sung J, Seo JS, Lee EK, Park YJ, Kim JI. Son HY, et al. Nat Commun. 2017 Jul 13;8:15966. doi: 10.1038/ncomms15966. Nat Commun. 2017. PMID: 28703219 Free PMC article.
- The clinicopathological significance and ethnic difference of FHIT hypermethylation in non-small-cell lung carcinoma: a meta-analysis and literature review.Wu X, Wu G, Yao X, Hou G, Jiang F. Wu X, et al. Drug Des Devel Ther. 2016 Feb 15;10:699-709. doi: 10.2147/DDDT.S85253. eCollection 2016. Drug Des Devel Ther. 2016. PMID: 26929601 Free PMC article. Review.
- The clinicopathological significance of FHIT hypermethylation in non-small cell lung cancer, a meta-analysis and literature review.Yan W, Xu N, Han X, Zhou XM, He B. Yan W, et al. Sci Rep. 2016 Jan 22;6:19303. doi: 10.1038/srep19303. Sci Rep. 2016. PMID: 26796853 Free PMC article. Review.
- Research Support, Non-U.S. Gov't
- Acid Anhydride Hydrolases / biosynthesis*
- Acid Anhydride Hydrolases / genetics
- Adenocarcinoma / genetics*
- Adenocarcinoma / pathology
- Adolescent
- Adult
- Aged
- DNA Methylation / genetics*
- Disease Progression
- Female
- Gene Expression
- Gene Expression Regulation, Neoplastic*
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Neoplasm Proteins / biosynthesis*
- Neoplasm Proteins / genetics
- Neoplasm Staging
- Polymerase Chain Reaction
- Promoter Regions, Genetic / genetics*
- Thyroid Neoplasms / genetics*
- Thyroid Neoplasms / pathology
- Young Adult
- Neoplasm Proteins
- fragile histidine triad protein
- Acid Anhydride Hydrolases
- Full Text Sources
- Medical
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2897109/bin/ijcep0003-0482-f5.jpg)
Source: PubMed