Interleukin-6 promotes the dedifferentiation of papillary thyroid cancer cells

in Endocrine-Related Cancer
Authors:
Guo-Qiang Zhang Department of Nuclear Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Search for other papers by Guo-Qiang Zhang in
Current site
Google Scholar
PubMed
Close
,
Chuang Xi Department of Nuclear Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Search for other papers by Chuang Xi in
Current site
Google Scholar
PubMed
Close
,
Chen-Tian Shen Department of Nuclear Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Search for other papers by Chen-Tian Shen in
Current site
Google Scholar
PubMed
Close
,
Hong-Jun Song Department of Nuclear Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Search for other papers by Hong-Jun Song in
Current site
Google Scholar
PubMed
Close
,
Quan-Yong Luo Department of Nuclear Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Search for other papers by Quan-Yong Luo in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-8778-5415
, and
Zhong-Ling Qiu Department of Nuclear Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Search for other papers by Zhong-Ling Qiu in
Current site
Google Scholar
PubMed
Close

Correspondence should be addressed to Q Luo or Z Qiu: luoqy@sjtu.edu.cn or qiuzhongling123@163.com

*(G-Q Zhang and C Xi contributed equally to this work)

Restricted access
Rent on DeepDyve

Sign up for journal news

Radioiodine treatment is a fundamental therapy for patients with papillary thyroid cancer (PTC). Sodium/iodide symporter (NIS)-mediated iodine uptake is a prerequisite for the efficacy of radioiodine therapy. Interleukin-6 (IL-6) is a pro-tumor cytokine, but its regulation of NIS expression in PTC has not been elucidated. In this study, we found that IL-6 enhanced the proliferation ability of PTC cells. Moreover, the negative association between IL-6 and NIS expression in thyroid cancer tissues was demonstrated. IL-6 downregulated thyroid-specific genes such as NIS, thyroid peroxidase, and thyroid-stimulating hormone receptor and thyroid-specific transcription factors including thyroid transcription factor-1 (TTF-1) and paired box protein-8 (PAX-8). The inhibitory effects of IL-6 on NIS expression were alleviated by mitogen-activated protein kinase and Janus kinase inhibitors. Depletion of c-Jun or STAT3 also rescued IL-6-induced NIS downregulation, with STAT3 depletion exerting a stronger effect. TTF-1 protein expression was also restored by depleting c-Jun or STAT3. STAT3 depletion, but not c-Jun depletion, alleviated the inhibitory effect of IL-6 on PAX-8 expression. Moreover, the downregulation of NIS by IL-6 was rescued by overexpressing TTF-1 and PAX-8. Tocilizumab, an IL-6 receptor blocker, did not have any cytostatic activity in PTC cells, and it also failed to induce redifferentiation in vitro. However, we found that the drug blocked the inhibitory effect of IL-6 on NIS expression. In summary, IL-6 inhibits NIS transcription in PTC cells by activating mitogen-activated protein kinase and Janus kinase signaling.

 

  • Collapse
  • Expand
  • Alraouji NN, Al-Mohanna FH, Ghebeh H, Arafah M, Almeer R, Al-Tweigeri T & & Aboussekhra A 2020 Tocilizumab potentiates cisplatin cytotoxicity and targets cancer stem cells in triple-negative breast cancer. Molecular Carcinogenesis 59 10411051. (https://doi.org/10.1002/mc.23234)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chai W, Ye F, Zeng L, Li Y & & Yang L 2019 HMGB1-mediated autophagy regulates sodium/iodide symporter protein degradation in thyroid cancer cells. Journal of Experimental and Clinical Cancer Research 38 325. (https://doi.org/10.1186/s13046-019-1328-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cunha LL, Domingues GAB, Morari EC, Soares FA, Vassallo J & & Ward LS 2021 The immune landscape of the microenvironment of thyroid cancer is closely related to differentiation status. Cancer Cell International 21 387. (https://doi.org/10.1186/s12935-021-02084-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, Caillou B, Ricard M, Lumbroso JD, De Vathaire F, et al.2006 Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. Journal of Clinical Endocrinology and Metabolism 91 28922899. (https://doi.org/10.1210/jc.2005-2838)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guo Y, Xu F, Lu T, Duan Z & & Zhang Z 2012 Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treatment Reviews 38 904910. (https://doi.org/10.1016/j.ctrv.2012.04.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, Pentlow KS, Zanzonico PB, Haque S, Gavane S, et al.2013 Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. New England Journal of Medicine 368 623632. (https://doi.org/10.1056/NEJMoa1209288)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hou P, Bojdani E & & Xing M 2010 Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways. Journal of Clinical Endocrinology and Metabolism 95 820828. (https://doi.org/10.1210/jc.2009-1888)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kobawala TP, Trivedi TI, Gajjar KK, Patel DH, Patel GH & & Ghosh NR 2016 Significance of interleukin-6 in papillary thyroid carcinoma. Journal of Thyroid Research 2016 6178921. (https://doi.org/10.1155/2016/6178921)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kogai T, Taki K & & Brent GA 2006 Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocrine-Related Cancer 13 797826. (https://doi.org/10.1677/erc.1.01143)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Koh SA & & Lee KH 2018 HGF-mediated S100A11 overexpression enhances proliferation and invasion of gastric cancer. American Journal of Translational Research 10 33853394.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kumari N, Dwarakanath BS, Das A & & Bhatt AN 2016 Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biology 37 1155311572. (https://doi.org/10.1007/s13277-016-5098-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li CW, Shi X, Ma B, Wang YL, Lu ZW, Liao T, Wang Y, Ji QH & & Wei WJ 2021 A 4 gene-based immune signature predicts dedifferentiation and immune exhaustion in thyroid cancer. Journal of Clinical Endocrinology and Metabolism 106 e3208–e3220. (https://doi.org/10.1210/clinem/dgab132)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li H, Dai H, Li H, Li B & & Shao Y 2019 Polymorphisms of the highly expressed IL-6 gene in the papillary thyroid cancer susceptibility among Chinese. Current Molecular Medicine 19 443451. (https://doi.org/10.2174/1566524019666190426142432)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lim H, Devesa SS, Sosa JA, Check D & & Kitahara CM 2017 Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA 317 13381348. (https://doi.org/10.1001/jama.2017.2719)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Little AS, Balmanno K, Sale MJ, Smith PD & & Cook SJ 2012 Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. Biochemical Society Transactions 40 7378. (https://doi.org/10.1042/BST20110647)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Na KJ & & Choi H 2018 Immune landscape of papillary thyroid cancer and immunotherapeutic implications. Endocrine-Related Cancer 25 523531. (https://doi.org/10.1530/ERC-17-0532)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Notarangelo T, Sisinni L, Trino S, Calice G, Simeon V & & Landriscina M 2018 IL6/STAT3 axis mediates resistance to BRAF inhibitors in thyroid carcinoma cells. Cancer Letters 433 147155. (https://doi.org/10.1016/j.canlet.2018.06.038)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oh JM & & Ahn BC 2021 Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS. Theranostics 11 62516277. (https://doi.org/10.7150/thno.57689)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sa R, Liang R, Qiu X, He Z, Liu Z & & Chen L 2022 IGF2BP2-dependent activation of ERBB2 signaling contributes to acquired resistance to tyrosine kinase inhibitor in differentiation therapy of radioiodine-refractory papillary thyroid cancer. Cancer Letters 527 1023. (https://doi.org/10.1016/j.canlet.2021.12.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Scheller J, Chalaris A, Schmidt-Arras D & & Rose-John S 2011 The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta 1813 878888. (https://doi.org/10.1016/j.bbamcr.2011.01.034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shen CT, Wei WJ, Qiu ZL, Song HJ & & Luo QY 2016 Afamin promotes glucose metabolism in papillary thyroid carcinoma. Molecular and Cellular Endocrinology 434 108115. (https://doi.org/10.1016/j.mce.2016.06.013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Spitzweg C, Joba W, Morris JC & & Heufelder AE 1999 Regulation of sodium iodide symporter gene expression in FRTL-5 rat thyroid cells. Thyroid 9 821830. (https://doi.org/10.1089/thy.1999.9.821)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tam S, Boonsripitayanon M, Amit M, Fellman BM, Li Y, Busaidy NL, Cabanillas ME, Dadu R, Sherman S, Waguespack SG, et al.2018 Survival in differentiated thyroid cancer: comparing the AJCC cancer staging seventh and eighth editions. Thyroid 28 13011310. (https://doi.org/10.1089/thy.2017.0572)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, Simeone DM, Zou W & & Welling TH 2014 Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147 13931404. (https://doi.org/10.1053/j.gastro.2014.08.039)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang X, Peng W, Li C, Qin R, Zhong Z & & Sun C 2021 Identification of an immune-related signature indicating the dedifferentiation of thyroid cells. Cancer Cell International 21 231. (https://doi.org/10.1186/s12935-021-01939-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wei WJ, Sun ZK, Shen CT, Song HJ, Zhang XY, Qiu ZL & & Luo QY 2017 Obatoclax and LY3009120 efficiently overcome vemurafenib resistance in differentiated thyroid cancer. Theranostics 7 9871001. (https://doi.org/10.7150/thno.17322)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wiltshire JJ, Drake TM, Uttley L & & Balasubramanian SP 2016 Systematic review of trends in the incidence rates of thyroid cancer. Thyroid 26 15411552. (https://doi.org/10.1089/thy.2016.0100)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xin Y, Shang X, Sun X, Liu Y, Xu G & & Xue G 2021 Trefoil factor 3 inhibits thyroid cancer cell progression related to IL-6/JAK/STAT3 signaling pathway. Evidence-Based Complementary and Alternative Medicine: eCAM 2021 2130229. (https://doi.org/10.1155/2021/2130229)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang GQ, Jiao Q, Shen CT, Song HJ, Zhang HZ, Qiu ZL & & Luo QY 2021a Interleukin 6 regulates the expression of programmed cell death ligand 1 in thyroid cancer. Cancer Science 112 9971010. (https://doi.org/10.1111/cas.14752)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang L, Xu S, Cheng X, Wu J, Wang X, Wu L, Yu H & & Bao J 2021b Curcumin enhances the membrane trafficking of the sodium iodide symporter and augments radioiodine uptake in dedifferentiated thyroid cancer cells via suppression of the PI3K-AKT signaling pathway. Food and Function 12 82608273. (https://doi.org/10.1039/d1fo01073e)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhao X, Ma W, Li X, Li H, Li J, Li H & & He F 2021 ANXA1 enhances tumor proliferation and migration by regulating epithelial-mesenchymal transition and IL-6/JAK2/STAT3 pathway in papillary thyroid carcinoma. Journal of Cancer 12 12951306. (https://doi.org/10.7150/jca.52171)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zheng R, Chen G, Li X, Wei X, Liu C & & Derwahl M 2019 Effect of IL-6 on proliferation of human thyroid anaplastic cancer stem cells. International Journal of Clinical and Experimental Pathology 12 39924001.

    • PubMed
    • Search Google Scholar
    • Export Citation