Expression of transcription and growth factors and the AKT/m-TOR signaling pathway components in papillary thyroid cancer

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Abstract

Background: The molecular mechanism of thyroid cancer development is associated with changes in expression of transcription factors and growth factors accompanied by modified level of the AKT/m-TOR components.

Aims. The aim of study was to determine NF-κB p65, NF-κB p50, HIF-1α, HIF-2α, VEGF, CAIX, VEGFR2 expression and mRNA level of the AKT/m-TOR signaling pathway components in papillary thyroid cancer compared to those in benign lesions.

Material and methods: Forty patients aged 33—66 years with T1-4N0-2M0 papillary thyroid cancer (7 males and 33 females) were enrolled in the study. The mean age was 52.0±2.6 years. The comparison group included patients with benign lesions of thyroid tissue (4 males and 18 females) aged 38—66 years (mean age, 53.0±4.4 years). Expression levels of NF-κB p65, NF-κB p50, HIF-1α, HIF-2α, VEGF, CAIX, VEGFR2, and the AKT/m-TOR signaling pathway components were determined by RT-PCR using specific primers.

Results: Increased expression of transcription factors NF-κB and HIF-2α was found in papillary thyroid cancer. The levels of AKT and PTEN mRNA were elevated in transformed tissues. c-Raf expression was reduced 2.1-fold in cancer compared to that in thyroid tissues with benign lesions. Multiple positive correlations were revealed between transcription and growth factors and the AKT/m-TOR signaling pathway components in cancer. An association between PTEN expression and the NF-κB mRNA level was revealed, being a sign of deregulation in the signaling cascade in cancer tissues.

Conclusions: Overexpression of NF-κB, HIF-2α, AKT, PTEN and reduction of c-Raf expression is typical of thyroid papillary cancer.

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About the authors

Liudmila V. Spirina

Tomsk National Research Medical Center of the Russian Academy of Sciences; Siberian State Medical University

Author for correspondence.
Email: spirinalv@oncology.tomsk.ru
ORCID iD: 0000-0002-5269-736X
SPIN-code: 1336-8363

MD, PhD

Russian Federation, 5, Kooperativny Str., Tomsk, 634009; 2, Moscowski Trakt, Tomsk, 634050

Sventlana Yu. Chizhevskaya

Tomsk National Research Medical Center of the Russian Academy of Sciences

Email: sch@oncology.tomsk.ru
ORCID iD: 0000-0003-2974-4778
SPIN-code: 9561-3382

MD, PhD

Russian Federation, 5, Kooperativny Str., Tomsk, 634009

Irina V. Kondakova

Tomsk National Research Medical Center of the Russian Academy of Sciences

Email: kondakova@oncology.tomsk.ru
ORCID iD: 0000-0003-0907-4615
SPIN-code: 9338-4149

MD, PhD, Professor

Russian Federation, 5, Kooperativny Str., Tomsk, 634009

References

  1. Злокачественные новообразования в России в 2015 г. (заболеваемость и смертность)/ Под ред. Каприна А.Д., Старинского В.В., Петровой Г.В. // М.: МНИОИ им. П.А. Герцена — Филиал ФГБУ «НМИРЦ» Минздрава России; 2017. [Kaprin AD, Starinsky VV, Petrova GV, Editors. Zlokachestvennye novoobrazovaniya v Rossii vV 2015 (zabolevaemost’ i smertnost’). Moscow: MNIOI im. P.A. Gertsena — Filial FGBU «NMIRTS» Minzdrava Rossii; 2017. (In Russ.)].
  2. Spirina LV, Usynin YA, Kondakova IV, et al. The Akt-MTOR signalling pathway in kidney cancer tissues. Aip Conf Proc. 2015; 1688:080004. doi: 10.1063/1.4936067
  3. Спирина Л.В., Усынин Е.А., Кондакова И.В., и др. Влияние таргетной терапии на содержание транскрипционных, ростовых факторов, протеинкиназы TOR и активности внутриклеточных протеиназ у больных диссеминированным раком почки. // Бюллетень экспериментальной биологии и медицины. — 2015. — Т. 60. — № 6. — C. 768—772. [Spirina LV, Usynin EA, Kondakova IV, et al. Effect of target therapy on the content of transcription and growth factors, protein kinase TOR, and activity of intracellular proteases in patients with metastatic renal cell carcinoma. Bull Eksp Biol Med. 2015;60(6):768-772. (In Russ.)].
  4. Спирина Л.В., Усынин Е.А., Юрмазов З.А., и др. Экспрессия МРНК и содержание Nf-kB, Hif-1, Hif-2, Vegf, Vegfr2 и арбоангидразы Ix при метастазировании рака почки. Молекулярная биология. — 2017. — Т. 51. — № 2. — С. 372—377. [Spirina LV, Usynin EA, YurmazovZA, et l. Transcription factors Nf-Kb, Hif-1, Hif-2, growth factor Vegf, Vegfr2 and carboanhydrase Ix MRNA and protein level in the development of kidney cancer metastasis. Molecular Biology. 2017;51(2):372-377. (In Russ.)]. doi: 10.7868/S0026898417020197
  5. Tanaka TN, Alloju SK, Oh DK, et al. Thyroid cancer: molecular pathogenesis, tyrosine kinase inhibitors, and other new therapies. Am J Hematol Oncol. 2015;11(4):5-9.
  6. Robbins HL, Hague A. The Pi3k/Akt pathway in tumors of endocrine tissues. Front Endocrinol (Lausanne). 2015;6:188. doi: 10.3389/Fendo.2015.00188
  7. Dodd KM, Yang J, Shen MH, et al. MTORC1 Drives Hif-1α and Vegf-a signalling via multiple mechanisms involving 4e-Bp1, S6k1 and Stat3. Oncogene. 2015;34(17):2239-2250. doi: 10.1038/onc.2014.164
  8. Бельцевич Д.Г., Ванушко В.Э., Мельниченко Г.А., и др. Российские клинические рекомендации по диагностике и лечению дифференцированного рака щитовидной железы у взрослых. Проект. Редакция 2016 г. // Эндокринная Хирургия. — 2015. — Т. 9. — № 3. — С. 7—17. [Bel’tsevich DG, Vanushko VE, Mel’nichenko GA, et al. Russian clinical practice guidelines for diagnosis and treatment of differentiated thyroid cancer. Endocrine Surgery. 2015;9(3):7-17. (In Russ.)]. doi: 10.14341/Serg201537-14
  9. Клинические рекомендации по диагностике и лечению рака щитовидной железы. / Под ред. Алиевой С.Б., Алымова Ю.В., Мудунова А.М., и др. — М. 2014. Доступно по http://www.Oncology.ru/Association/Clinical-Guidelines/2014/56.Pdf. Ссылка активна на 22.09.14. [Alieva SB, Alymov YuV, Mudunov AM, Editors. Clinical recommendations for the diagnosis and treatment of thyroid cancer. Ed by Podvyaznikov SO, Kropotov MA. Moscow. 2007. (In Russ)]. Dostupno po://www.Oncology.ru/Association/Clinical-Guidelines/2014/56.Pdf. Accessed 22.09.14
  10. Magnon C, Opolon P, Ricard M, et al. Radiation and inhibition of angiogenesis by canstatin synergize to induce HIFα-mediated tumor apoptotic switch. J Clin Invest. 2007;117(7):1844-1855. doi: 10.1172/jci30269
  11. Burrows N, Babur M, Resch J, et al. Hypoxia-inducible factor in thyroid carcinoma. J Thyroid Res. 2011;2011:762905. doi: 10.4061/2011/762905
  12. Vasko V. Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer. J Med Genet. 2004;41(3):161-170. doi: 10.1136/jmg.2003.015339
  13. Krzeslak A, Pomorski L, Lipinska A. Expression, localization, and phosphorylation of Akt1 in benign and malignant thyroid lesions. Endocr Pathol. 2011;22(4):206-211. doi: 10.1007/s12022-011-9177-4
  14. Beg S, Siraj AK, Jehan Z, et al. PTEN loss is associated with follicular variant of middle eastern papillary thyroid carcinoma. Br J Cancer. 2015;112(12):1938-1943. doi: 10.1038/bjc.2015.169
  15. Lee J, Jeong S, Park JH, et al. Aberrant expression of cot is related to recurrence of papillary thyroid cancer. Medicine (Baltimore). 2015;94(6):E548. doi: 10.1097/Md.0000000000000548
  16. Alverdi V, Hetrick B, Joseph S, Komives EA. Direct observation of a transient ternary complex during kappabalpha-mediated dissociation of Nf-Kappab from DNA. Proc Natl Acad Sci USA. 2014;111(1):225-230. doi: 10.1073/Pnas.1318115111
  17. Potoyan DA, Zheng W, Komives EA, Wolynes PG. Molecular stripping in the Nf-Kappab/Ikappab/DNA genetic regulatory network. Proc Natl Acad Sci USA. 2016;113(1):110-115. doi: 10.1073/Pnas.1520483112
  18. Liu YM, Ying SP, Huang YR, et al. Expression of HIF-1alpha and HIF-2alpha correlates to biological and clinical significance in papillary thyroid carcinoma. World J Surg Oncol. 2016;14(1):30. doi: 10.1186/S12957-016-0785-9
  19. LV Y, Sun Y, Shi T, et al. Pigment epithelium-derived factor HAS a role in the progression of papillary thyroid carcinoma by affecting the Hif1alpha-Vegf signaling pathway. Oncol Lett. 2016;12(6):5217-5222. doi: 10.3892/Ol.2016.5316
  20. Chalhoub N, Baker SJ. PTEN and the Pi3-kinase pathway in cancer. Annu Rev Pathol. 2009;4:127-150. doi: 10.1146/Annurev.Pathol.4.110807.092311
  21. Vasudevan KM, Gurumurthy S, Rangnekar VM. Suppression of PTEN expression by Nf-B prevents apoptosis. Mol Cell Biol. 2004;24(3):1007-1021. doi: 10.1128/Mcb.24.3.1007-1021.2004
  22. Koul D, Takada Y, Shen R, et al. PTEN enhances TNF-induced apoptosis through modulation of nuclear factor-Kappab signaling pathway in human glioma cells. Biochem Biophys Res Commun. 2006;350(2):463-471. doi: 10.1016/J.Bbrc.2006.09.077

Supplementary files

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1. Fig. 1. The relationship between transcriptional and growth factors in papillary thyroid carcinoma. Lines denote direct bonds between molecular markers.

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2. Fig. 2. Scatter plot between PTEN expression and NF-κB p65 expression.

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3. Fig. 3. Scatter plot between PTEN expression and NF-κB p50 expression.

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Copyright (c) 2021 Spirina L.V., Chizhevskaya S.Y., Kondakova I.V.

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