Reactivated thyroid hormone receptor β attenuates anaplastic thyroid cancer (ATC) stem cell activity

in Endocrine-Related Cancer
Authors:
Xuguang Zhu Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA

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Li Zhao Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA

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Woo Kyung Lee Doolittle Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA

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https://orcid.org/0000-0002-6737-3173
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Sheue-yann Cheng Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA

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https://orcid.org/0000-0003-3530-2386

Correspondence should be addressed to S Cheng: chengs@mail.nih.gov
DOI:
https://doi.org/10.1530/ERC-22-0306
Volume/Issue:
Volume 30: Issue 6
Article Type:
Research Article
Article ID:
e220306
Online Publication Date:
02 May 2023
Copyright:
© the author(s) 2023
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Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity contributes to therapeutic resistance and recurrence of ATC. We show that the expression of the endogenous thyroid hormone receptor β gene (THRB) is silenced in ATC and demonstrate that the exogenously expressed TRβ suppresses CSC activity. Decitabine is one of the demethylation agents to treat myelodysplastic syndrome and acute myeloid leukemia patients and is currently in clinical trials for hematopoietic malignancies and solid tumors. We aim to show that the re-expression of the endogenous THRB gene by decitabine can attenuate CSC activity to block ATC tumor growth. We treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRβ on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRβ, as evidenced by western blot and immunohistochemical analyses. The expressed TRβ inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44, and β-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation, and increasing apoptosis. Our findings suggest that re-expression of the endogenous TRβ is a novel therapeutic approach for ATC via suppression of CSC activity.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© the author(s) 2023
Article ID:
e220306
Received Date:
24 Feb 2023
Accepted Date:
20 Mar 2023
Print Publication Date:
01 Jun 2023
Online Publication Date:
02 May 2023
Keywords:
anaplastic thyroid cancer; thyroid hormone receptor β; cancer stem cells; demethylation agents; decitabine; DAC; cancer stem cell markers

  • Aghajani MJ, Cooper A, McGuire H, Jeffries T, Saab J, Ismail K, de Souza P, Bray V, Fazekas de St Groth B, Niles N, et al.2019 Pembrolizumab for anaplastic thyroid cancer: a case study. Cancer Immunology, Immunotherapy 68 1921–1934. (https://doi.org/10.1007/s00262-019-02416-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ando S, Sarlis NJ, Oldfield EH & & Yen PM 2001 Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. Journal of Clinical Endocrinology and Metabolism 86 5572–5576. (https://doi.org/10.1210/jcem.86.11.7984)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bolf EL, Gillis NE, Davidson CD, Rodriguez PD, Cozzens L, Tomczak JA, Frietze S & & Carr FE 2020 Thyroid hormone receptor beta induces a tumor-suppressive program in anaplastic thyroid cancer. Molecular Cancer Research 18 1443–1452. (https://doi.org/10.1158/1541-7786.MCR-20-0282)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cheng SY, Leonard JL & & Davis PJ 2010 Molecular aspects of thyroid hormone actions. Endocrine Reviews 31 139–170. (https://doi.org/10.1210/er.2009-0007)

  • Davidson CD, Gillis NE & & Carr FE 2021 Thyroid hormone receptor beta as tumor suppressor: untapped potential in treatment and diagnostics in solid tumors. Cancers (Basel) 13 4254. (https://doi.org/10.3390/cancers13174254)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dunwell TL, Hesson LB, Pavlova T, Zabarovska V, Kashuba V, Catchpoole D, Chiaramonte R, Brini AT, Griffiths M, Maher ER, et al.2009 Epigenetic analysis of childhood acute lymphoblastic leukemia. Epigenetics 4 185–193. (https://doi.org/10.4161/epi.4.3.8752)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Horkko TT, Tuppurainen K, George SM, Jernvall P, Karttunen TJ & & Makinen MJ 2006 Thyroid hormone receptor beta1 in normal colon and colorectal cancer-association with differentiation, polypoid growth type and K-ras mutations. International Journal of Cancer 118 1653–1659. (https://doi.org/10.1002/ijc.21556)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Iwasaki Y, Sunaga N, Tomizawa Y, Imai H, Iijima H, Yanagitani N, Horiguchi K, Yamada M & & Mori M 2010 Epigenetic inactivation of the thyroid hormone receptor beta1 gene at 3p24.2 in lung cancer. Annals of Surgical Oncology 17 2222–2228. (https://doi.org/10.1245/s10434-010-0956-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jerzak KJ, Cockburn JG, Dhesy-Thind SK, Pond GR, Pritchard KI, Nofech-Mozes S, Sun P, Narod SA & & Bane A 2018 Thyroid hormone receptor beta-1 expression in early breast cancer: a validation study. Breast Cancer Research and Treatment 171 709–717. (https://doi.org/10.1007/s10549-018-4844-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Joseph B, Ji M, Liu D, Hou P & & Xing M 2007 Lack of mutations in the thyroid hormone receptor (TR) alpha and beta genes but frequent hypermethylation of the TRbeta gene in differentiated thyroid tumors. Journal of Clinical Endocrinology and Metabolism 92 4766–4770. (https://doi.org/10.1210/jc.2007-0812)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kamiya Y, Puzianowska-Kuznicka M, McPhie P, Nauman J, Cheng SY & & Nauman A 2002 Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma. Carcinogenesis 23 25–33. (https://doi.org/10.1093/carcin/23.1.25)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankratz DG, Wynshaw-Boris A, Refetoff S, et al.2000 Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. PNAS 97 13209–13214. (https://doi.org/10.1073/pnas.230285997)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim WG, Zhu X, Kim DW, Zhang L, Kebebew E & & Cheng SY 2013 Reactivation of the silenced thyroid hormone receptor beta gene expression delays thyroid tumor progression. Endocrinology 154 25–35. (https://doi.org/10.1210/en.2012-1728)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kondo T, Ezzat S & & Asa SL 2006 Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nature Reviews. Cancer 6 292–306. (https://doi.org/10.1038/nrc1836)

  • Kondo T, Nakazawa T, Ma D, Niu D, Mochizuki K, Kawasaki T, Nakamura N, Yamane T, Kobayashi M & & Katoh R 2009 Epigenetic silencing of TTF-1/NKX2-1 through DNA hypermethylation and histone H3 modulation in thyroid carcinomas. Laboratory Investigation; a Journal of Technical Methods and Pathology 89 791–799. (https://doi.org/10.1038/labinvest.2009.50)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, et al.2016 Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. Journal of Clinical Investigation 126 1052–1066. (https://doi.org/10.1172/JCI85271)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, et al.2006 Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9 391–403. (https://doi.org/10.1016/j.ccr.2006.03.030)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee WK, Zhu X, Park S, Zhu YJ, Zhao L, Meltzer P & & Cheng SY 2022 Regulation of cancer stem cell activity by thyroid hormone receptor beta. Oncogene 41 2315–2325. (https://doi.org/10.1038/s41388-022-02242-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li Z, Meng ZH, Chandrasekaran R, Kuo WL, Collins CC, Gray JW & & Dairkee SH 2002 Biallelic inactivation of the thyroid hormone receptor beta1 gene in early stage breast cancer. Cancer Research 62 1939–1943.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lin HY, Chin YT, Shih YJ, Chen YR, Leinung M, Keating KA, Mousa SA & & Davis PJ 2018 In tumor cells, thyroid hormone analogues non-immunologically regulate PD-L1 and PD-1 accumulation that is anti-apoptotic. Oncotarget 9 34033–34037. (https://doi.org/10.18632/oncotarget.26143)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lin KH, Shieh HY, Chen SL & & Hsu HC 1999 Expression of mutant thyroid hormone nuclear receptors in human hepatocellular carcinoma cells. Molecular Carcinogenesis 26 53–61. (https://doi.org/10.1002/(sici)1098-2744(199909)26:1<53::aid-mc7>3.0.co;2-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ling Y, Xu X, Hao J, Ling X, Du X, Liu X & & Zhao X 2010 Aberrant methylation of the THRB gene in tissue and plasma of breast cancer patients. Cancer Genetics and Cytogenetics 196 140–145. (https://doi.org/10.1016/j.cancergencyto.2009.09.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Luongo C, Porcelli T, Sessa F, De Stefano MA, Scavuzzo F, Damiano V, Klain M, Bellevicine C, Matano E, Troncone G, et al.2021 Combination of lenvatinib and pembrolizumab as salvage treatment for paucicellular variant of anaplastic thyroid cancer: a case report. Current Oncology 28 5401–5407. (https://doi.org/10.3390/curroncol28060450)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marlow LA, D'Innocenzi J, Zhang Y, Rohl SD, Cooper SJ, Sebo T, Grant C, McIver B, Kasperbauer JL, Wadsworth JT, et al.2010 Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target. Journal of Clinical Endocrinology and Metabolism 95 5338–5347. (https://doi.org/10.1210/jc.2010-1421)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Martin TD, Patel RS, Cook DR, Choi MY, Patil A, Liang AC, Li MZ, Haigis KM & & Elledge SJ 2021 The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science 373 1327–1335. (https://doi.org/10.1126/science.abg5784)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Miasaki FY, Vivaldi A, Ciampi R, Agate L, Collecchi P, Capodanno A, Pinchera A & & Elisei R 2008 Retinoic acid receptor beta2 re-expression and growth inhibition in thyroid carcinoma cell lines after 5-aza-2'-deoxycytidine treatment. Journal of Endocrinological Investigation 31 724–730. (https://doi.org/10.1007/BF03346422)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mohamed FEZA, Abdelaziz AO, Kasem AH, Ellethy T & & Gayyed MF 2021 Thyroid hormone receptor alpha1 acts as a new squamous cell lung cancer diagnostic marker and poor prognosis predictor. Scientific Reports 11 7944. (https://doi.org/10.1038/s41598-021-86754-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Molinaro E, Romei C, Biagini A, Sabini E, Agate L, Mazzeo S, Materazzi G, Sellari-Franceschini S, Ribechini A, Torregrossa L, et al.2017 Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies. Nature Reviews. Endocrinology 13 644–660. (https://doi.org/10.1038/nrendo.2017.76)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Montesinos MDM & & Pellizas CG 2019 Thyroid hormone action on innate immunity. Frontiers in Endocrinology (Lausanne) 10 350. (https://doi.org/10.3389/fendo.2019.00350)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nabhan F, Kander E, Shen R, Agrawal A, Sukrithan V, Zhou Y, Goyal A, Roll K, Shah M & & Konda B 2021 Pembrolizumab in a patient with treatment-naive unresectable BRAF-mutation negative anaplastic thyroid cancer. Case Reports in Endocrinology 2021 5521649. (https://doi.org/10.1155/2021/5521649)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pozdeyev N, Gay LM, Sokol ES, Hartmaier R, Deaver KE, Davis S, French JD, Borre PV, LaBarbera DV, Tan AC, et al.2018 Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clinical Cancer Research 24 3059–3068. (https://doi.org/10.1158/1078-0432.CCR-18-0373)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Reynolds BA & & Weiss S 1992 Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255 1707–1710. (https://doi.org/10.1126/science.1553558)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Russo D, Damante G, Puxeddu E, Durante C & & Filetti S 2011 Epigenetics of thyroid cancer and novel therapeutic targets. Journal of Molecular Endocrinology 46 R73–R81. (https://doi.org/10.1530/JME-10-0150)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sigalotti L, Fratta E, Coral S, Cortini E, Covre A, Nicolay HJ, Anzalone L, Pezzani L, Di Giacomo AM, Fonsatti E, et al.2007 Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications. Journal of Cellular Physiology 212 330–344. (https://doi.org/10.1002/jcp.21066)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Silva JM, Dominguez G, Gonzalez-Sancho JM, Garcia JM, Silva J, Garcia-Andrade C, Navarro A, Munoz A & & Bonilla F 2002 Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene 21 4307–4316. (https://doi.org/10.1038/sj.onc.1205534)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, Kebebew E, Lee NY, Nikiforov YE, Rosenthal MS, et al.2012 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 22 1104–1139. (https://doi.org/10.1089/thy.2012.0302)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, Wen PY, Zielinski C, Cabanillas ME, Urbanowitz G, et al.2018 Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. Journal of Clinical Oncology 36 7–13. (https://doi.org/10.1200/JCO.2017.73.6785)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tuttle RM, Haugen B & & Perrier ND 2017 Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System for Differentiated and Anaplastic Thyroid Cancer (Eighth Edition): What changed and why? Thyroid 27 751–756. (https://doi.org/10.1089/thy.2017.0102)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vivaldi A, Miasaki FY, Ciampi R, Agate L, Collecchi P, Capodanno A, Pinchera A & & Elisei R 2009 Re-differentiation of thyroid carcinoma cell lines treated with 5-Aza-2'-deoxycytidine and retinoic acid. Molecular and Cellular Endocrinology 307 142–148. (https://doi.org/10.1016/j.mce.2009.03.020)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yanatatsaneejit P, Chalertpet K, Sukbhattee J, Nuchcharoen I, Phumcharoen P & & Mutirangura A 2020 Promoter methylation of tumor suppressor genes induced by human papillomavirus in cervical cancer. Oncology Letters 20 955–961. (https://doi.org/10.3892/ol.2020.11625)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yang YSH, Ko PJ, Pan YS, Lin HY, Whang-Peng J, Davis PJ & & Wang K 2021 Role of thyroid hormone-integrin alphavbeta3-signal and therapeutic strategies in colorectal cancers. Journal of Biomedical Science 28 24. (https://doi.org/10.1186/s12929-021-00719-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yen PM 2001 Physiological and molecular basis of thyroid hormone action. Physiological Reviews 81 1097–1142. (https://doi.org/10.1152/physrev.2001.81.3.1097)

  • Zhu X, Holmsen E, Park S, Willingham MC, Qi J & & Cheng SY 2018 Synergistic effects of BET and MEK inhibitors promote regression of anaplastic thyroid tumors. Oncotarget 9 35408–35421. (https://doi.org/10.18632/oncotarget.26253)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu X, Park S, Lee WK & & Cheng SY 2019 Potentiated anti-tumor effects of BETi by MEKi in anaplastic thyroid cancer. Endocrine-Related Cancer 26 739–750. (https://doi.org/10.1530/ERC-19-0107)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu XG, Zhao L, Willingham MC & & Cheng SY 2010 Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma. Oncogene 29 1909–1919. (https://doi.org/10.1038/onc.2009.476)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zuo H, Gandhi M, Edreira MM, Hochbaum D, Nimgaonkar VL, Zhang P, Dipaola J, Evdokimova V, Altschuler DL & & Nikiforov YE 2010 Downregulation of Rap1GAP through epigenetic silencing and loss of heterozygosity promotes invasion and progression of thyroid tumors. Cancer Research 70 1389–1397. (https://doi.org/10.1158/0008-5472.CAN-09-2812)

    • PubMed
    • Search Google Scholar
    • Export Citation