The Interplay Between Epithelial-Mesenchymal Transition (EMT) and the Thyroid Hormones-αvβ3 Axis in Ovarian Cancer

Weingarten, C; Jenudi, Yonatan; Tshuva, Rami Yair; Moskovich, Dotan; Alfandari, Adi; Hercbergs, Aleck; Davis, Paul J.; Ellis, Martin; Ashur‐Fabian, Osnat

doi:10.1007/s12672-017-0316-3

Cited by 32 publications

(33 citation statements)

References 78 publications

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“…Recently, the interplay between epithelial-mesenchymal transition (EMT) and the thyroid hormones-αvβ3 axis in ovarian cancer was investigated (Weingarten et al 2018). It was shown that the transcription of mesenchymal markers, β-catenin, zeb-1, slug/snail, vimentin, and n-cadherin was hardly affected by T3 and T4, while that of the epithelial markers, e-cadherin and zo-1, and was inhibited after treatment with thyroid hormones.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Ditsch

Heublein

Jeschke

et al. 2020

J Cancer Res Clin Oncol

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Purpose Thyroid hormone receptors (THR) have manifold functions and are involved in the carcinogenesis of several tumor types. Within this study, we aimed to investigate the expression pattern (nuclear versus cytoplasmic) of the THR alpha and its impact on patients survival in ovarian cancer (OvCa). Methods The presence of the thyroid hormone receptors THRα, THRα1 and − 2 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated with clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS). Results Among all subtypes of OvCa, clear cell carcinomas showed the highest THRα expression. Furthermore, nuclear THRα was associated with a reduced survival in this subtype. However, nuclear expressed THRα1 turned out to be a positive prognosticator for all subtypes of OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. In contrast, cytoplasmic expression THRα2 was associated with a reduced OS in all subtypes of OvCa patients; while, cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates with gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin. Conclusion Depending on nuclear or cytoplasmic expression, our study shows that THRα and its isoforms 1 and 2 provide different prognostic information for ovarian cancer patients. Further investigations should analyze if THRs may represent new endocrine targets for the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Ditsch

Heublein

Jeschke

et al. 2020

J Cancer Res Clin Oncol

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“…The link of thyroid hormone, particularly T4, to the EMT has recently been examined [ 17 ]. EMT is a cog in the mechanism of metastasis, accounting for the genesis of cells capable of metastasizing [ 33 ].…”

Section: Cancer Metastasis-relevant Molecular Mechanisms Of Thyroimentioning

confidence: 99%

“…Integrin αvβ3 and its T4 receptor have also been implicated in the process of cancer metastasis [ 16 , 17 , 18 ]. Tetrac in its small molecule formulation acts as a T4 antagonist at the αvβ3 integrin [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Contributions of Thyroid Hormone to Cancer Metastasis

et al. 2018

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Acting at a cell surface receptor on the extracellular domain of integrin αvβ3, thyroid hormone analogues regulate downstream the expression of a large panel of genes relevant to cancer cell proliferation, to cancer cell survival pathways, and to tumor-linked angiogenesis. Because αvβ3 is involved in the cancer cell metastatic process, we examine here the possibility that thyroid hormone as l-thyroxine (T4) and the thyroid hormone antagonist, tetraiodothyroacetic acid (tetrac), may respectively promote and inhibit metastasis. Actions of T4 and tetrac that are relevant to cancer metastasis include the multitude of synergistic effects on molecular levels such as expression of matrix metalloproteinase genes, angiogenesis support genes, receptor tyrosine kinase (EGFR/ERBB2) genes, specific microRNAs, the epithelial–mesenchymal transition (EMT) process; and on the cellular level are exemplified by effects on macrophages. We conclude that the thyroid hormone-αvβ3 interaction is mechanistically linked to cancer metastasis and that modified tetrac molecules have antimetastatic activity with feasible therapeutic potential.

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“…It was found that the transcription of mesenchymal markers, β-catenin, zeb-1, slug/snail, vimentin, and n-cadherin was hardly affected by T3 and T4, while that of the epithelial markers, e-cadherin and zo-1, and was inhibited after treatment with thyroid hormones. These results suggest a novel role for the thyroid hormone-αvβ3 axis in EMT, with possible implications for ovarian cancer metastasis [47].…”

Section: Discussionmentioning

confidence: 78%

“…Recently, the interplay between epithelial-mesenchymal transition (EMT) and the thyroid hormones-αvβ3 axis in ovarian cancer was investigated [47]. It was found that the transcription of mesenchymal markers, β-catenin, zeb-1, slug/snail, vimentin, and n-cadherin was hardly affected by T3 and T4, while that of the epithelial markers, e-cadherin and zo-1, and was inhibited after treatment with thyroid hormones.…”

Section: Discussionmentioning

confidence: 99%

THR alpha and its subtypes alpha1 and alpha2 are prognostic markers for survival of ovarian cancer patients

Ditsch¹,

Heublein²,

Jeschke³

et al. 2019

Preprint

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Background Ovarian cancer is most lethal in comparison to all other gynecological cancer cases. Within this study, we aimed to investigate the expression of the thyroid hormone receptor alpha and its influence on patient survival in ovarian cancer (OvCa). Methods The presence of the thyroid hormone receptors THRα, THRα1 and -2 were investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated to clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS). Results Patients with clear cell OvCa showed the highest THRα expression and nuclear THRα expression is associated with reduced survival in this group. In contrast, nuclear expressed THRα1 is a positive prognosticator for all OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. Cytoplasmic expression of THRα2 accompanies with reduced OS in all OvCa patients, whereas cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates to gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin. Conclusion Thyroid hormones promote ovarian cancer cell proliferation. The further investigation of thyroid hormones and its specific receptors offer the possibility to investigate new endocrine targets against ovarian cancer.

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The Interplay Between Epithelial-Mesenchymal Transition (EMT) and the Thyroid Hormones-αvβ3 Axis in Ovarian Cancer

Cited by 32 publications

References 78 publications

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Contributions of Thyroid Hormone to Cancer Metastasis

THR alpha and its subtypes alpha1 and alpha2 are prognostic markers for survival of ovarian cancer patients

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