Molecular Understanding of RET/PTC-Mediated Thyroid Carcinogenesis

  • Young Suk Jo
  • Dong Wook Kim
  • Min Hee Lee
  • Soung Jung Kim
  • Jung Hwan Hwang
  • Minho Shong
Conference paper


Differentiated thyroid cancers, including papillary and follicular carcinomas, frequently develop as a result of genetic alterations. Papillary thyroid cancers (PTC) show balanced inversions or translocations that usually involve the 3.0-kb intron 11 of the tyrosine kinase receptor protein RET. These rearrangements result in the formation of RET/PTC through the fusion of the tyrosine kinase domain of the RET proto-oncogene with the 5′-end of activating heterologous sequences belonging to the RET-fused genes. RET/PTC has been reported to be a constitutively active kinase in thyroid epithelial cells. Although RET/PTC has intrinsic tyrosine kinase activity, the direct substrates of RET/PTC in thyroid cells are largely unknown. We have examined the interaction of RET/PTC and Signal transducer and activator of transcription-3 (STAT3), and the phosphorylation activity of RET/ PTC on the Y705 residue of STAT3. STAT3 is a direct substrate for RET/PTC tyrosine kinase, and Y705 phosphorylation in STAT3 by RET/PTC is a critical signaling pathway for the specific induction of genes in the RET/PTC-mediated transformation process. Here we show that LKB1 act as a suppressor of STAT3 in RET/PTC-mediated processes of transformation. The mutations of LKB1 protein kinase in humans results in a disorder termed Peutz-Jeghers syndrome (PJS), which predisposes to a wide spectrum of benign and malignant tumors. LKB1?+/??heterozygous mice develop tumors resembling those found in human PJS. The overexpression of LKB1 in LKB1-defi cient cancer cells induced a G1 cell-cycle arrest, and genetic studies in Caenorhabditis elegans, Drosophila, and Xenopus have indicated that the LKB1 homologue in these organisms plays a role in regulating cell polarity. We have reported that RET/PTC is able to activate STAT3 and that it is involved in transformation in thyroid carcinogenesis. The wild-type and kinase dead mutant LKB1 decreased STAT3 transcriptional activity in RET/PTCtransfected cells. LKB1 showed interactions with STAT3 in immunoprecipitation experiments. The LKB1 and activated STAT3 colocalized within the nucleus. The GAL4-fused LKB1 showed intrinsic repressor activities. However, the repressor activities were not affected by treatment of HDAC inhibitors.


Vascular Endothelial Growth Factor Papillary Thyroid Cancer Vascular Endothelial Growth Factor Promoter Thyroid Epithelial Cell Endogenous STAT3 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Santoro M, Melillo RM, Carlomagno F, et al (2002) Molecular mechanisms of RET activation in human cancer. Ann N Y Acad Sci 963:116–121PubMedCrossRefGoogle Scholar
  2. 2.
    Grieco M, Santoro M, Berlingieri MT, et al (1990) PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563PubMedCrossRefGoogle Scholar
  3. 3.
    Pierotti MA, Bongarzone I, Borello MG, et al (1996) Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 16:1–14PubMedCrossRefGoogle Scholar
  4. 4.
    Santoro M, Chiappetta G, Cerrato A, et al (1996) Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–1826PubMedGoogle Scholar
  5. 5.
    Besset V, Scott RP, Ibanez CF (2000) Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase. J Biol Chem 275:39159–39166PubMedCrossRefGoogle Scholar
  6. 6.
    Chiariello M, Visconti R, Carlomagno F, et al (1998) Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKS): evidence for a divergence of the ERKs and JNKs pathways induced by Ret. Oncogene 16:2435–2445PubMedCrossRefGoogle Scholar
  7. 7.
    Segouffi n-Cariou C, Billaud M (2000) Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J Biol Chem 275:3568–3576CrossRefGoogle Scholar
  8. 8.
    Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95–98PubMedCrossRefGoogle Scholar
  9. 9.
    Bromberg JF (2001) Activation of STAT proteins and growth control. Bioessays 23: 161–169PubMedCrossRefGoogle Scholar
  10. 10.
    Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473PubMedCrossRefGoogle Scholar
  11. 11.
    Bromberg JF, Wrzeszczynska MH, Devgan G, et al (1999) Stat3 as an oncogene. Cell 98:295–303PubMedCrossRefGoogle Scholar
  12. 12.
    Cao X, Tay A, Guy GR, et al (1996) Activation and association of Stat3 with Src in v-Srctransformed cell lines. Mol Cell Biol 16:1595–1603PubMedGoogle Scholar
  13. 13.
    Bromberg JF, Horvath CM, Besser D, et al (1998) Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 18:2553–2558PubMedGoogle Scholar
  14. 14.
    Bardeesy N, Sinha M, Hezel AF, et al (2002) Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature (Lond) 419:162–167PubMedCrossRefGoogle Scholar
  15. 15.
    Rossi DJ, Ylikorkala A, Korsisaari N, et al (2002) Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc Natl Acad Sci U S A 99:12327–12332PubMedCrossRefGoogle Scholar
  16. 16.
    Hwang JH, Kim DW, Suh JM, et al (2003) Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation. Mol Endocrinol 17:1155–1166PubMedCrossRefGoogle Scholar
  17. 17.
    Braga-Basaria M, Ringel MD (2003) Clinical review 158. Beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer. J Clin Endocrinol Metab 88: 1947–1960PubMedCrossRefGoogle Scholar
  18. 18.
    Carlomagno F, Vitagliano D, Guida T, et al (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, effi ciently blocks oncogenic RET kinases. Cancer Res 62: 7284–7290PubMedGoogle Scholar
  19. 19.
    Fagin JA (2002) Perspective: lessons learned from molecular genetic studies of thyroid cancer. Insights into pathogenesis and tumor-specific therapeutic targets. Endocrinology 143: 2025–2028PubMedCrossRefGoogle Scholar
  20. 20.
    Mendel DB, Laird AD, Xin X, et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337PubMedGoogle Scholar
  21. 21.
    O’Farrell AM, Abrams TJ, Yuen HA, et al (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597–3605PubMedCrossRefGoogle Scholar
  22. 22.
    Turner HE, Harris AL, Melmed S, et al (2003) Angiogenesis in endocrine tumors. Endocr Rev 24:600–632PubMedCrossRefGoogle Scholar
  23. 23.
    Boudeau J, Kieloch A, Alessi DR, et al (2003) Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers syndrome patients. Hum Mutat 21:172PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang J, Yang J, Roy SK, et al (2003) The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci U S A 100:9342–9347PubMedCrossRefGoogle Scholar
  25. 25.
    Sun L, Tran N, Liang C, et al (1999) Design, synthesis, and evaluations of substituted 3-[(3-or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases. J Med Chem 42:5120–5130PubMedCrossRefGoogle Scholar
  26. 26.
    Smolich BD, Yuen HA, West KA, et al (2001) The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 97:1413–1421PubMedCrossRefGoogle Scholar
  27. 27.
    Chung J, Park ES, Kim D, et al (2000) Thyrotropin modulates interferon-gamma-mediated intercellular adhesion molecule-1 gene expression by inhibiting Janus kinase-1 and signal transducer and activator of transcription-1 activation in thyroid cells. Endocrinology 141: 2090–2097PubMedCrossRefGoogle Scholar
  28. 28.
    Park ES, Kim H, Suh JM, et al (2000) Thyrotropin induces SOCS-1 (suppressor of cytokine signaling-1) and SOCS-3 in FRTL-5 thyroid cells. Mol Endocrinol 14:440–448PubMedCrossRefGoogle Scholar
  29. 29.
    Kim DW, Jo YS, Jung HS, et al (2006) An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 91:4070–4076PubMedCrossRefGoogle Scholar
  30. 30.
    Barone MV, Sepe L, Melillo RM, et al (2001) RET/PTC1 oncogene signaling in PC Cl 3 thyroid cells requires the small GTP-binding protein Rho. Oncogene 20:6973–6982PubMedCrossRefGoogle Scholar
  31. 31.
    Schuringa JJ, Wojtachnio K, Hagens W, et al (2001) MEN2A-RET-induced cellular transformation by activation of STAT3. Oncogene 20:5350–5358PubMedCrossRefGoogle Scholar
  32. 32.
    Kim DW, Hwang JH, Suh JM, et al (2003) RET/PTC (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (PDK1): an alternative phosphatidylinositol 3-kinase-independent pathway to activate PDK1. Mol Endocrinol 17:1382–1394PubMedCrossRefGoogle Scholar
  33. 33.
    Aaronson DS, Horvath CM (2002) A road map for those who don’t know JAK-STAT. Science 296:1653–1655PubMedCrossRefGoogle Scholar
  34. 34.
    Hwang ES, Kim DW, Hwang JH, et al (2004) Regulation of signal transducer and activator of transcription 1 (STAT1) and STAT1-dependent genes by RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncogenic tyrosine kinases. Mol Endocrinol 18:2672–2684PubMedCrossRefGoogle Scholar
  35. 35.
    Hemminki A, Markie D, Tomlinson I, et al (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature (Lond) 391:184–187PubMedCrossRefGoogle Scholar
  36. 36.
    Ho JM, Beattie BK, Squire JA, et al (1999) Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. Blood 93:4354–4364PubMedGoogle Scholar
  37. 37.
    Tiainen M, Vaahtomeri K, Ylikorkala A, et al (2002) Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). Hum Mol Genet 11:497–1504CrossRefGoogle Scholar
  38. 38.
    Tiainen M, Ylikorkala A, Makela TP (1999) Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. Proc Natl Acad Sci U S A 96:9248–9251PubMedCrossRefGoogle Scholar
  39. 39.
    Marignani PA, Kanai F, Carpenter CL (2001) LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. J Biol Chem 276:32415–32418PubMedCrossRefGoogle Scholar
  40. 40.
    Lufei C, Ma J, Huang G, et al (2003) GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J 22:1325–1335PubMedCrossRefGoogle Scholar
  41. 41.
    Chung CD, Liao J, Liu B, et al (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278:1803–1805PubMedCrossRefGoogle Scholar
  42. 42.
    Smith JK, Mamoon NM, Duhe RJ (2004) Emerging roles of targeted small molecule proteintyrosine kinase inhibitors in cancer therapy. Oncol Res 14:175–225PubMedGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Young Suk Jo
    • 1
  • Dong Wook Kim
    • 1
  • Min Hee Lee
    • 1
  • Soung Jung Kim
    • 1
  • Jung Hwan Hwang
    • 1
  • Minho Shong
    • 1
  1. 1.Department of Internal Medicine, Laboratory of Endocrine Cell BiologyChungnam National University School of MedicineDaejeonKorea

Personalised recommendations