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Article: Dysregulation of clathrin promotes thyroid cell growth and contributes to multinodular goiter pathogenesis

TitleDysregulation of clathrin promotes thyroid cell growth and contributes to multinodular goiter pathogenesis
Authors
Issue Date2015
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/issn/09254439
Citation
Biochimica et Biophysica Acta - Molecular Basis of Disease, 2015, v. 1852 n. 8, p. 1676-1686 How to Cite?
AbstractA germline mutation (A339V) in thyroid transcription factor-1 (TITF1/NKX2.1) was shown to be associated with multinodular goiter (MNG) and papillary thyroid carcinoma (PTC) pathogenesis. The overexpression of A339V TTF1 significantly promoted hormone-independent growth of the normal thyroid cells, representing a cause of MNG and/or PTC. Nevertheless, the underlying mechanism still remains unclear. In this study, we used liquid chromatography (LC)-tandem mass spectrometry (MS/MS)-based shotgun proteomics comparing the global protein expression profiles of normal thyroid cells (PCCL3) that overexpressed the wild-type or A339V TTF1 to identify key proteins implicated in this process. Proteomic pathway analysis revealed that the aberrant activation of epidermal growth factor (EGF) signaling is significantly associated with the overexpression of A339V TTF1 in PCCL3, and clathrin heavy chain (Chc) is the most significantly up-regulated protein of the pathway. Intriguingly, dysregulated Chc expression facilitated a nuclear accumulation of pStat3, leading to an enhanced cell proliferation of the A339V clones. Down-regulation and abrogation of Chc-mediated cellular trafficking, respectively, by knocking-down Chc and ectopic expression of a dominant-negative (DN) form of Chc could significantly reduce the nuclear pStat3 and rescue the aberrant cell proliferation of the A339V clones. Subsequent expression analysis further revealed that CHC and pSTAT3 are co-overexpressed in 66.7% (10/15) MNG. Taken together, our results suggest that the A339V TTF1 mutant protein up-regulates the cellular expression of Chc, resulting in a constitutive activation of Stat3 pathway, and prompting the aberrant growth of thyroid cells. This extensive growth signal may promote the development of MNG. Copyright © 2015 Elsevier B.V. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/210688
ISSN
2015 Impact Factor: 5.158
2015 SCImago Journal Rankings: 2.718

 

DC FieldValueLanguage
dc.contributor.authorLau, ST-
dc.contributor.authorZhou, T-
dc.contributor.authorLiu, JA-
dc.contributor.authorFung, EYM-
dc.contributor.authorChe, CM-
dc.contributor.authorLang, HHB-
dc.contributor.authorNgan, ESW-
dc.date.accessioned2015-06-23T05:47:04Z-
dc.date.available2015-06-23T05:47:04Z-
dc.date.issued2015-
dc.identifier.citationBiochimica et Biophysica Acta - Molecular Basis of Disease, 2015, v. 1852 n. 8, p. 1676-1686-
dc.identifier.issn0925-4439-
dc.identifier.urihttp://hdl.handle.net/10722/210688-
dc.description.abstractA germline mutation (A339V) in thyroid transcription factor-1 (TITF1/NKX2.1) was shown to be associated with multinodular goiter (MNG) and papillary thyroid carcinoma (PTC) pathogenesis. The overexpression of A339V TTF1 significantly promoted hormone-independent growth of the normal thyroid cells, representing a cause of MNG and/or PTC. Nevertheless, the underlying mechanism still remains unclear. In this study, we used liquid chromatography (LC)-tandem mass spectrometry (MS/MS)-based shotgun proteomics comparing the global protein expression profiles of normal thyroid cells (PCCL3) that overexpressed the wild-type or A339V TTF1 to identify key proteins implicated in this process. Proteomic pathway analysis revealed that the aberrant activation of epidermal growth factor (EGF) signaling is significantly associated with the overexpression of A339V TTF1 in PCCL3, and clathrin heavy chain (Chc) is the most significantly up-regulated protein of the pathway. Intriguingly, dysregulated Chc expression facilitated a nuclear accumulation of pStat3, leading to an enhanced cell proliferation of the A339V clones. Down-regulation and abrogation of Chc-mediated cellular trafficking, respectively, by knocking-down Chc and ectopic expression of a dominant-negative (DN) form of Chc could significantly reduce the nuclear pStat3 and rescue the aberrant cell proliferation of the A339V clones. Subsequent expression analysis further revealed that CHC and pSTAT3 are co-overexpressed in 66.7% (10/15) MNG. Taken together, our results suggest that the A339V TTF1 mutant protein up-regulates the cellular expression of Chc, resulting in a constitutive activation of Stat3 pathway, and prompting the aberrant growth of thyroid cells. This extensive growth signal may promote the development of MNG. Copyright © 2015 Elsevier B.V. All rights reserved.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/issn/09254439-
dc.relation.ispartofBiochimica et Biophysica Acta - Molecular Basis of Disease-
dc.titleDysregulation of clathrin promotes thyroid cell growth and contributes to multinodular goiter pathogenesis-
dc.typeArticle-
dc.identifier.emailZhou, T: twzhou@hku.hk-
dc.identifier.emailFung, EYM: eva.fungym@hku.hk-
dc.identifier.emailChe, CM: cmche@hku.hk-
dc.identifier.emailLang, HHB: blang@hkucc.hku.hk-
dc.identifier.emailNgan, ESW: engan@hku.hk-
dc.identifier.authorityFung, EYM=rp01986-
dc.identifier.authorityChe, CM=rp00670-
dc.identifier.authorityLang, HHB=rp01828-
dc.identifier.authorityNgan, ESW=rp00422-
dc.identifier.doi10.1016/j.bbadis.2015.05.005-
dc.identifier.pmid25981745-
dc.identifier.hkuros243576-
dc.identifier.hkuros248598-
dc.identifier.volume1852-
dc.identifier.issue8-
dc.identifier.spage1676-
dc.identifier.epage1686-
dc.publisher.placeNetherlands-

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