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Journal of Endocrinological Investigation

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Open Access 21-07-2023 | Testosterone | Original Article

Testosterone promotes the migration, invasion and EMT process of papillary thyroid carcinoma by up-regulating Tnnt1

Authors: C. Jiang, F. Xu, D. Yi, B. Jiang, R. Wang, L. Wu, H. Ding, J. Qin, Y. Lee, J. Sang, X. Shi, L. Su

Published in: Journal of Endocrinological Investigation | Issue 1/2024

Abstract

Purpose

To explore the key genes and molecular pathways in the progression of thyroid papillary carcinoma (PTC) promoted by testosterone using RNA-sequencing technology, and to provide new drug targets for improving the therapeutic effect of PTC.

Methods

Orchiectomy (ORX) was carried out to construct ORX mouse models. TPC-1 cells were subcutaneously injected for PTC formation in mice, and the tumor tissues were collected for RNA-seq. The key genes were screened by bioinformatics technology. Tnnt1 expression in PTC cells was knocked down or overexpressed by transfection. Cell counting kit-8 (CCK-8), colony formation assay, scratch assay and transwell assay were adopted, respectively, for the detection of cell proliferation, colony formation, migration and invasion. Besides, quantification real-time polymerase chain reaction (qRT-PCR) and western blot were utilized to determine the mRNA and protein expression levels of genes in tissues or cells.

Results

Both estradiol and testosterone promoted the growth of PTC xenografts. The key gene Tnnt1 was screened and obtained by bioinformatics technology. Functional analysis revealed that overexpression of Tnnt1 could markedly promote the proliferation, colony formation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process of PTC cells, as well as could activate p38/JNK pathway. In addition, si-Tnt1 was able to inhibit the cancer-promoting effect of testosterone.

Conclusion

Based on the outcomes of bioinformatics and basic experiments, it is found that testosterone can promote malignant behaviors such as growth, migration, invasion and EMT process of PTC by up-regulating Tnnt1 expression. In addition, the function of testosterone may be achieved by activating p38/JNK signaling pathway.

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Lin P, Guo YN, Shi L, Li XJ, Yang H, He Y, Li Q, Dang YW, Wei KL, Chen G (2019) Development of a prognostic index based on an immunogenomic landscape analysis of papillary thyroid cancer. Aging (Albany NY) 11:480–500. https://doi.org/10.18632/aging.101754CrossRefPubMed

Liu H, Chen X, Lin T, Chen X, Yan J, Jiang S (2019) MicroRNA-524-5p suppresses the progression of papillary thyroid carcinoma cells via targeting on FOXE1 and ITGA3 in cell autophagy and cycling pathways. J Cell Physiol 234:18382–18391. https://doi.org/10.1002/jcp.28472CrossRefPubMedPubMedCentral

Stark R, Grzelak M, Hadfield J (2019) RNA sequencing: the teenage years. Nat Rev Genet 20:631–656. https://doi.org/10.1038/s41576-019-0150-2CrossRefPubMed

Dong W, Horiuchi K, Tokumitsu H, Sakamoto A, Noguchi E, Ueda Y, Okamoto T (2019) Time-varying pattern of mortality and recurrence from papillary thyroid cancer: lessons from a long-term follow-up. Thyroid 29:802–808. https://doi.org/10.1089/thy.2018.0128CrossRefPubMed

Ortega J, Sala C, Flor B, Lledo S (2004) Efficacy and cost-effectiveness of the UltraCision harmonic scalpel in thyroid surgery: an analysis of 200 cases in a randomized trial. J Laparoendosc Adv Surg Tech A 14:9–12. https://doi.org/10.1089/109264204322862289CrossRefPubMed

Suteau V, Munier M, Briet C, Rodien P (2021) Sex bias in differentiated thyroid cancer. Int J Mol Sci. https://doi.org/10.3390/ijms222312992CrossRefPubMedPubMedCentral

Morgentaler A, Traish A (2020) The history of testosterone and the evolution of its therapeutic potential. Sex Med Rev 8:286–296. https://doi.org/10.1016/j.sxmr.2018.03.002CrossRefPubMed

Auerbach JM, Khera M (2022) Testosterone replacement therapy and cardiovascular disease. Int J Impot Res 34:685–690. https://doi.org/10.1038/s41443-021-00516-6CrossRefPubMed

Barbonetti A, D’Andrea S, Francavilla S (2020) Testosterone replacement therapy. Andrology 8:1551–1566. https://doi.org/10.1111/andr.12774CrossRefPubMed

10.

Kelly DM, Jones TH (2013) Testosterone: a metabolic hormone in health and disease. J Endocrinol 217:R25-45. https://doi.org/10.1530/JOE-12-0455CrossRefPubMed

11.

Kumar A, Klinge CM, Goldstein RE (2010) Estradiol-induced proliferation of papillary and follicular thyroid cancer cells is mediated by estrogen receptors alpha and beta. Int J Oncol 36:1067–1080. https://doi.org/10.3892/ijo_00000588CrossRefPubMed

12.

Banu KS, Govindarajulu P, Aruldhas MM (2001) Testosterone and estradiol have specific differential modulatory effect on the proliferation of human thyroid papillary and follicular carcinoma cell lines independent of TSH action. Endocr Pathol 12:315–327. https://doi.org/10.1385/ep:12:3:315CrossRefPubMed

13.

Miro C, Di Giovanni A, Murolo M, Cicatiello AG, Nappi A, Sagliocchi S, Di Cicco E, Morra F, Celetti A, Pacifico F, Imbimbo C, Crocetto F, Dentice M (2022) Thyroid hormone and androgen signals mutually interplay and enhance inflammation and tumorigenic activation of tumor microenvironment in prostate cancer. Cancer Lett 532:215581. https://doi.org/10.1016/j.canlet.2022.215581CrossRefPubMed

14.

Nakazawa M, Kyprianou N (2017) Epithelial-mesenchymal-transition regulators in prostate cancer: androgens and beyond. J Steroid Biochem Mol Biol 166:84–90. https://doi.org/10.1016/j.jsbmb.2016.05.007CrossRefPubMed

15.

Nouri M, Ratther E, Stylianou N, Nelson CC, Hollier BG, Williams ED (2014) Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention. Front Oncol 4:370. https://doi.org/10.3389/fonc.2014.00370CrossRefPubMedPubMedCentral

16.

Ceder Y, Bjartell A, Culig Z, Rubin MA, Tomlins S, Visakorpi T (2016) The molecular evolution of castration-resistant prostate cancer. Eur Urol Focus 2:506–513. https://doi.org/10.1016/j.euf.2016.11.012CrossRefPubMed

17.

Zheng Y, Li P, Huang H, Ye X, Chen W, Xu G, Zhang F (2021) Androgen receptor regulates eIF5A2 expression and promotes prostate cancer metastasis via EMT. Cell Death Discov 7:373. https://doi.org/10.1038/s41420-021-00764-xCrossRefPubMedPubMedCentral

18.

Mitchell B, Dhingra JK, Mahalingam M (2016) BRAF and epithelial–mesenchymal transition: lessons from papillary thyroid carcinoma and primary cutaneous melanoma. Adv Anat Pathol 23:244–271. https://doi.org/10.1097/PAP.0000000000000113CrossRefPubMed

19.

Pastushenko I, Blanpain C (2019) EMT transition states during tumor progression and metastasis. Trends Cell Biol 29:212–226. https://doi.org/10.1016/j.tcb.2018.12.001CrossRefPubMed

20.

Liu CZ, Guo WP, Peng JB, Chen G, Lin P, Huang XL, Liu XF, Yang H, He Y, Pang YY, Ma W (2020) Clinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues. Adv Med Sci 65:442–456. https://doi.org/10.1016/j.advms.2020.09.001CrossRefPubMed

21.

Valkenburg KC, Amend SR, Pienta KJ (2016) Murine prostate micro-dissection and surgical castration. J Vis Exp. https://doi.org/10.3791/53984CrossRefPubMedPubMedCentral

22.

Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, Imamichi T, Chang W (2022) DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. https://doi.org/10.1093/nar/gkac194CrossRefPubMedPubMedCentral

23.

Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, Doncheva NT, Legeay M, Fang T, Bork P, Jensen LJ, von Mering C (2021) The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 49:D605–D612. https://doi.org/10.1093/nar/gkaa1074CrossRef

24.

Jin JP, Zhang Z, Bautista JA (2008) Isoform diversity, regulation, and functional adaptation of troponin and calponin. Crit Rev Eukaryot Gene Expr 18:93–124. https://doi.org/10.1615/critreveukargeneexpr.v18.i2.10CrossRefPubMed

25.

Kuroda T, Yasuda S, Nakashima H, Takada N, Matsuyama S, Kusakawa S, Umezawa A, Matsuyama A, Kawamata S, Sato Y (2017) Identification of a gene encoding slow skeletal muscle troponin T as a novel marker for immortalization of retinal pigment epithelial cells. Sci Rep 7:8163. https://doi.org/10.1038/s41598-017-08014-wCrossRefPubMedPubMedCentral

26.

Shi Y, Zhao Y, Zhang Y, AiErken N, Shao N, Ye R, Lin Y, Wang S (2018) TNNT1 facilitates proliferation of breast cancer cells by promoting G1/S phase transition. Life Sci 208:161–166. https://doi.org/10.1016/j.lfs.2018.07.034CrossRefPubMed

27.

Chen Y, Wang J, Wang D, Kang T, Du J, Yan Z, Chen M (2020) TNNT1, negatively regulated by miR-873, promotes the progression of colorectal cancer. J Gene Med 22:e3152. https://doi.org/10.1002/jgm.3152CrossRefPubMed

28.

Hao YH, Yu SY, Tu RS, Cai YQ (2020) TNNT1, a prognostic indicator in colon adenocarcinoma, regulates cell behaviors and mediates EMT process. Biosci Biotechnol Biochem 84:111–117. https://doi.org/10.1080/09168451.2019.1664891CrossRefPubMed

29.

Peluso I, Yarla NS, Ambra R, Pastore G, Perry G (2019) MAPK signalling pathway in cancers: olive products as cancer preventive and therapeutic agents. Semin Cancer Biol 56:185–195. https://doi.org/10.1016/j.semcancer.2017.09.002CrossRefPubMed

30.

Luo YH, Zhang L, Wang MY, Fang J, Xia JY, Yu XL (2021) Anti-cancer effects of baicalein on cervical carcinoma cells through down-regulation of the ERK/p38/MAPK pathway. J Biol Regul Homeost Agents 35:945–952. https://doi.org/10.23812/21-52-ACrossRefPubMed

31.

Wang Y, Zhou M, Shang D (2020) Berberine inhibits human gastric cancer cell growth via deactivation of p38/JNK pathway, induction of mitochondrial-mediated apoptosis, caspase activation and NF-kappaB inhibition. J BUON 25:314–318PubMed

32.

Ji KY, Kim KM, Kim YH, Shim KS, Lee JY, Kim T, Chae S (2021) Serum starvation sensitizes anticancer effect of Anemarrhena asphodeloides via p38/JNK-induced cell cycle arrest and apoptosis in colorectal cancer cells. Am J Chin Med 49:1001–1016. https://doi.org/10.1142/S0192415X21500488CrossRefPubMed

33.

Chen X, Hao A, Li X, Ye K, Zhao C, Yang H, Ma H, Hu L, Zhao Z, Hu L, Ye F, Sun Q, Zhang H, Wang H, Yao X, Fang Z (2020) Activation of JNK and p38 MAPK mediated by ZDHHC17 drives glioblastoma multiforme development and malignant progression. Theranostics 10:998–1015. https://doi.org/10.7150/thno.40076CrossRefPubMedPubMedCentral

34.

Grassi ES, Vezzoli V, Negri I, Labadi A, Fugazzola L, Vitale G, Persani L (2015) SP600125 has a remarkable anticancer potential against undifferentiated thyroid cancer through selective action on ROCK and p53 pathways. Oncotarget 6:36383–36399. https://doi.org/10.18632/oncotarget.5799CrossRefPubMedPubMedCentral

35.

Liao T, Qu N, Shi RL, Guo K, Ma B, Cao YM, Xiang J, Lu ZW, Zhu YX, Li DS, Ji QH (2017) BRAF-activated LncRNA functions as a tumor suppressor in papillary thyroid cancer. Oncotarget 8:238–247CrossRefPubMed

36.

Cui D, Zhao Y, Xu J (2019) Activation of CXCL5-CXCR2 axis promotes proliferation and accelerates G1 to S phase transition of papillary thyroid carcinoma cells and activates JNK and p38 pathways. Cancer Biol Ther 20:608–616. https://doi.org/10.1080/15384047.2018.1539289CrossRefPubMed

Title: Testosterone promotes the migration, invasion and EMT process of papillary thyroid carcinoma by up-regulating Tnnt1
Authors: C. Jiang
F. Xu
D. Yi
B. Jiang
R. Wang
L. Wu
H. Ding
J. Qin
Y. Lee
J. Sang
X. Shi
L. Su
Publication date: 21-07-2023
Publisher: Springer International Publishing
Keywords: Testosterone
Estradiol
Published in: Journal of Endocrinological Investigation / Issue 1/2024
Electronic ISSN: 1720-8386
DOI: https://doi.org/10.1007/s40618-023-02132-1

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