Top

Published in:

01-01-2022 | Thyroid Cancer | Original Article

NCOA3 is a critical oncogene in thyroid cancer via the modulation of major signaling pathways

Published in: Endocrine | Issue 1/2022

Abstract

Purpose

The Nuclear Receptor Coactivator (NCOA3, also known as SRC-3, AIB1, p/CIP, RAC3, ACTR, and TRAM1), acts as an oncogene in multiple tumors, but its biological function in thyroid cancer remains unclear. This study was designed to explore the role of NCOA3 in thyroid cancer.

Methods

The study assessed NCOA3 expression in thyroid cancer and their matched non-cancerous thyroid tissues at mRNA and protein levels. Then we evaluated the effect of NCOA3 on malignant activities of thyroid cancer cells. To better understand the oncogenic role of NCOA3 in thyroid tumorigenesis, we tested the effect of NCOA3 on major proteins related to thyroid cancer.

Results

Our data demonstrated that protein expression of NCOA3 was significantly upregulated in thyroid cancer tissues. NCOA3 knockdown inhibited cell proliferation and invasion, and induced cell cycle arrest and apoptosis in thyroid cancer. Conversely, ectopic expression of NCOA3 promoted cell proliferation and invasiveness in thyroid cancer. Mechanistically, NCOA3 could improve the survival and invasiveness of thyroid cancer cells through the modulation of the ErbB, AKT, ERK, and β-catenin pathways.

Conclusion

Collectively, these findings suggest that NCOA3 is critical in the initiation and development of thyroid cancer, and might be a possible marker for prognosis and therapy.

Available only for authorised users

F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J. Clin 68(6), 394–424 (2018). https://doi.org/10.3322/caac.21492CrossRef

L. Davies, H.G. Welch, Current thyroid cancer trends in the United States. JAMA Otolaryngol. Head. Neck Surg. 140(4), 317–322 (2014). https://doi.org/10.1001/jamaoto.2014.1CrossRefPubMed

Integrated genomic characterization of papillary thyroid carcinoma. Cell 159(3), 676–690 (2014). https://doi.org/10.1016/j.cell.2014.09.050

I. Landa, T. Ibrahimpasic, L. Boucai, R. Sinha, J.A. Knauf, R.H. Shah, S. Dogan, J.C. Ricarte-Filho, G.P. Krishnamoorthy, B. Xu, N. Schultz, M.F. Berger, C. Sander, B.S. Taylor, R. Ghossein, I. Ganly, J.A. Fagin, Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Investig. 126(3), 1052–1066 (2016). https://doi.org/10.1172/jci85271CrossRefPubMedPubMedCentral

M. Xing, Molecular pathogenesis and mechanisms of thyroid cancer. Nat. Rev. Cancer 13(3), 184–199 (2013). https://doi.org/10.1038/nrc3431CrossRefPubMedPubMedCentral

A. Satelli, S. Li, Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol. Life Sci. 68(18), 3033–3046 (2011). https://doi.org/10.1007/s00018-011-0735-1CrossRefPubMedPubMedCentral

X. Ye, R. Weinberg, Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25(11), 675–686 (2015). https://doi.org/10.1016/j.tcb.2015.07.012CrossRefPubMedPubMedCentral

N. Cho, C. Lin, E. Whang, A. Carothers, F. Moore, D. Ruan, Sulindac reverses aberrant expression and localization of beta-catenin in papillary thyroid cancer cells with the BRAFV600E mutation. Thyroid 20(6), 615–622 (2010). https://doi.org/10.1089/thy.2009.0415CrossRefPubMed

M. Xing, B.R. Haugen, M. Schlumberger, Progress in molecular-based management of differentiated thyroid cancer. Lancet 381(9871), 1058–1069 (2013). https://doi.org/10.1016/s0140-6736(13)60109-9CrossRefPubMedPubMedCentral

10.

J. Xu, R.C. Wu, B.W. O’Malley, Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat. Rev. Cancer 9(9), 615–630 (2009). https://doi.org/10.1038/nrc2695CrossRefPubMedPubMedCentral

11.

S.L. Anzick, J. Kononen, R.L. Walker, D.O. Azorsa, M.M. Tanner, X.Y. Guan, G. Sauter, O.P. Kallioniemi, J.M. Trent, P.S. Meltzer, AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277(5328), 965–968 (1997)CrossRef

12.

H.J. Zhou, J. Yan, W. Luo, G. Ayala, S.H. Lin, H. Erdem, M. Ittmann, S.Y. Tsai, M.J. Tsai, SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res. 65(17), 7976–7983 (2005). https://doi.org/10.1158/0008-5472.can-04-4076CrossRefPubMed

13.

H. Sakaguchi, J. Fujimoto, W.S. Sun, T. Tamaya, Clinical implications of steroid receptor coactivator (SRC)-3 in uterine endometrial cancers. J. Steroid Biochem Mol. Biol. 104(3-5), 237–240 (2007). https://doi.org/10.1016/j.jsbmb.2007.03.007CrossRefPubMed

14.

Y. Li, Q. Yang, H. Guan, B. Shi, M. Ji, P. Hou, ZNF677 suppresses Akt phosphorylation and tumorigenesis in thyroid cancer. Cancer Res. 78(18), 5216–5228 (2018). https://doi.org/10.1158/0008-5472.Can-18-0003CrossRefPubMed

15.

J. Shi, Y. Qu, X. Li, F. Sui, D. Yao, Q. Yang, B. Shi, M. Ji, P. Hou, Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer. Cell Death Dis. 7(10), e2442 (2016). https://doi.org/10.1038/cddis.2016.346CrossRefPubMedPubMedCentral

16.

D.J. Mulholland, S. Dedhar, G.A. Coetzee, C.C. Nelson, Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocr. Rev. 26(7), 898–915 (2005). https://doi.org/10.1210/er.2003-0034CrossRefPubMed

17.

M.K. Gule, Y. Chen, D. Sano, M.J. Frederick, G. Zhou, M. Zhao, Z.L. Milas, C.E. Galer, Y.C. Henderson, S.A. Jasser, D.L. Schwartz, J.A. Bankson, J.N. Myers, S.Y. Lai, Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model. Clin. Cancer Res. 17(8), 2281–2291 (2011). https://doi.org/10.1158/1078-0432.Ccr-10-2762CrossRefPubMedPubMedCentral

18.

C.L. Arteaga, J.A. Engelman, ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25(3), 282–303 (2014). https://doi.org/10.1016/j.ccr.2014.02.025CrossRefPubMedPubMedCentral

19.

R.E. Weiss, H.E. Ramos, Thyroid hormone receptor subtypes and their interaction with steroid receptor coactivators. Vitam. Horm. 68, 185–207 (2004). https://doi.org/10.1016/s0083-6729(04)68006-xCrossRefPubMed

20.

S.K. Lee, H.J. Kim, J.W. Kim, J.W. Lee, Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. Mol. Endocrinol. 13(11), 1924–1933 (1999). https://doi.org/10.1210/mend.13.11.0365CrossRefPubMed

21.

S.K. Lee, H.J. Kim, S.Y. Na, T.S. Kim, H.S. Choi, S.Y. Im, J.W. Lee, Steroid receptor coactivator-1 coactivates activating protein-1-mediated transactivations through interaction with the c-Jun and c-Fos subunits. J. Biol. Chem. 273(27), 16651–16654 (1998). https://doi.org/10.1074/jbc.273.27.16651CrossRefPubMed

22.

M.C. Louie, J.X. Zou, A. Rabinovich, H.W. Chen, ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance. Mol. Cell. Biol. 24(12), 5157–5171 (2004). https://doi.org/10.1128/mcb.24.12.5157-5171.2004CrossRefPubMedPubMedCentral

23.

S. Werbajh, I. Nojek, R. Lanz, M.A. Costas, RAC-3 is a NF-kappa B coactivator. FEBS Lett. 485(2-3), 195–199 (2000)CrossRef

24.

K.A. Sheppard, K.M. Phelps, A.J. Williams, D. Thanos, C.K. Glass, M.G. Rosenfeld, M.E. Gerritsen, T. Collins, Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1. J. Biol. Chem. 273(45), 29291–29294 (1998). https://doi.org/10.1074/jbc.273.45.29291CrossRefPubMed

25.

S. Giraud, F. Bienvenu, S. Avril, H. Gascan, D.M. Heery, O. Coqueret, Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a. J. Biol. Chem. 277(10), 8004–8011 (2002). https://doi.org/10.1074/jbc.M111486200CrossRefPubMed

26.

A. Arimura, M. vn Peer, A. Schröder, P. Rothman, The transcriptional co-activator p/CIP (NCoA-3) is up-regulated by STAT6 and serves as a positive regulator of transcriptional activation by STAT6. J. Biol. Chem. 279(30), 31105–31112 (2004). https://doi.org/10.1074/jbc.M404428200CrossRefPubMed

27.

H. Yu, D. Pardoll, R. Jove, STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9(11), 798–809 (2009). https://doi.org/10.1038/nrc2734CrossRefPubMedPubMedCentral

28.

L. Cao, Z. Wang, J. Ma, J. Chen, H. Zhu, X. Zhou, Q. Zhu, J. Dong, Q. Lan, Q. Huang, Clinical characteristics and molecular pathology of skull ectopic thyroid cancer. Ann. Transl. Med. 4(23), 462 (2016). https://doi.org/10.21037/atm.2016.12.19CrossRefPubMedPubMedCentral

29.

K. Shiraiwa, M. Matsuse, Y. Nakazawa, T. Ogi, K. Suzuki, V. Saenko, S. Xu, K. Umezawa, S. Yamashita, K. Tsukamoto, N. Mitsutake, JAK/STAT3 and NF-κB signaling pathways regulate cancer stem-cell properties in anaplastic thyroid cancer cells. Thyroid 29(5), 674–682 (2019). https://doi.org/10.1089/thy.2018.0212CrossRefPubMed

30.

T. Lahusen, M. Fereshteh, A. Oh, A. Wellstein, A. Riegel, Epidermal growth factor receptor tyrosine phosphorylation and signaling controlled by a nuclear receptor coactivator, amplified in breast cancer 1. Cancer Res. 67(15), 7256–7265 (2007). https://doi.org/10.1158/0008-5472.Can-07-1013CrossRefPubMedPubMedCentral

31.

Y. Yarden, G. Pines, The ERBB network: at last, cancer therapy meets systems biology. Nat. Rev. Cancer 12(8), 553–563 (2012). https://doi.org/10.1038/nrc3309CrossRefPubMed

32.

H. Clevers, R. Nusse, Wnt/β-catenin signaling and disease. Cell 149(6), 1192–1205 (2012). https://doi.org/10.1016/j.cell.2012.05.012CrossRefPubMed

33.

W.J. Jeong, E.J. Ro, K.Y. Choi, Interaction between Wnt/β-catenin and RAS-ERK pathways and an anti-cancer strategy via degradations of β-catenin and RAS by targeting the Wnt/β-catenin pathway. NPJ Precis Oncol. 2(1), 5 (2018). https://doi.org/10.1038/s41698-018-0049-yCrossRefPubMedPubMedCentral

34.

T. Hu, C. Li, Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol. Cancer 9, 236 (2010). https://doi.org/10.1186/1476-4598-9-236CrossRefPubMedPubMedCentral

35.

A.D. Rohira, D.M. Lonard, Steroid receptor coactivators present a unique opportunity for drug development in hormone-dependent cancers. Biochem Pharmacol. 140, 1–7 (2017). https://doi.org/10.1016/j.bcp.2017.04.005CrossRefPubMed

Title: NCOA3 is a critical oncogene in thyroid cancer via the modulation of major signaling pathways
Publication date: 01-01-2022
Keywords: Thyroid Cancer
Thyroid Cancer
Thyroid Cancer
Published in: Endocrine / Issue 1/2022
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-021-02819-6

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

NCOA3 is a critical oncogene in thyroid cancer via the modulation of major signaling pathways

Abstract

Purpose

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2022

Effect of very low-calorie ketogenic diet in combination with omega-3 on inflammation, satiety hormones, body composition, and metabolic markers. A pilot study in class I obese subjects

Occurrence and response to treatment of Graves’ disease after COVID vaccination in two male patients

A long noncoding RNA–microRNA expression signature predicts metastatic signature in pheochromocytomas and paragangliomas

Gestational diabetes mellitus in women born small or preterm: Systematic review and meta-analysis

Predictors of the effectiveness of insulin pumps in patients with type 1 diabetes mellitus

Incidence and predictive factors of postoperative hypocalcaemia according to type of thyroid surgery in older adults

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page