抑制BRAF基因对甲状腺癌摄碘率以及相关基因的影响
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摘要
目的:本实验研究了变异BRAF基因以及野生型BRAF基因对于甲状腺癌细胞的的摄碘率以及摄碘率相关基因的影响。
方法:在表达BRAF变异的甲状腺乳头状癌细胞系K1和表达野生型BRAF的甲状腺滤泡状癌细胞系RO82-W-1中,用RNA干扰技术敲除K1细胞系和RO82-W-1细胞系的BRAF基因,检测NIS,TSHR以及摄碘率的变化。结果:在甲状腺乳头状癌K1中,通过抑制了BRAF基因,观察到BRAF相关基因和蛋白的表达含量减少,而其NIS,TSHR的表达含量增高,同时摄碘率增高,而在甲状腺滤泡状癌细胞系RO82-W-1中,抑制BRAF基因后,其NIS,THSR以及摄碘率却没有明显变化。
结论:抑制变异的BRAF基因能够增加甲状腺乳头状癌的摄碘率以及相关基因的表达,而在表达正常BRAF基因的细胞中抑制其表达,则不能相应的增加其摄碘率以及相关基因的表达,可以说明BRAF基因的变异,以及BRAF蛋白的表达增多,能够导致甲状腺癌细胞摄碘率的降低,使着甲状腺癌向去分化的过程进展。
Objective: We research the effect of mutation BRAF gene and BRAF-wt to iodine uptake and relative gene in the thyroid carcinoma cell individually.
Methods: In the papillary thyroid carcinoma cell line K1 which express mutation BRAF, we knockdown BRAF gene by the special shRNA, then observe the change of capacity of iodine uptake with radiative I125 and the expressin of relative gene and protein of thyroid stimulating hormone receptor (TSHR) and Sodium iodide symporter (NIS), and knockdown BRAF gene in the follicular thyroid cancer which express BRAF-wt,we determine the expression of NIS,TSHR and capacity of iodine uptake with radiative I125.
Result: In the investigation,we found the phenomenon that the capacity of iodine uptake increases while BRAF DNA and protein diminishs in papillary thyroid carcinoma which expresses the mutatant BRAF,meanwhile the expression of NIS and TSHR increase. However, in follicular thyroid cancer RO82-W-1, after inhibition the expression of BRAF, we could not find the change of expression of NIS,TSHR and capacity of iodine uptake with radiative I125.
Conclusion: The mutation of BRAF gene could increase the iodine uptake and relative gene in papillary thyroid cancer which express the mutation BRAF, but in follicular thyroid cancer, inhibition BRAF could not influence NIS, TSHR and iodine uptake. The research indicates that mutation BRAF gene induce the loss of capacity of iodine uptake and promote the progress of didifferentiation of thyroid cancer. Mutation BRAF is patient to be a new target of genetic therapy to the thyriod cancer which is insensitive to radiative therapy.
方法:在表达BRAF变异的甲状腺乳头状癌细胞系K1和表达野生型BRAF的甲状腺滤泡状癌细胞系RO82-W-1中,用RNA干扰技术敲除K1细胞系和RO82-W-1细胞系的BRAF基因,检测NIS,TSHR以及摄碘率的变化。结果:在甲状腺乳头状癌K1中,通过抑制了BRAF基因,观察到BRAF相关基因和蛋白的表达含量减少,而其NIS,TSHR的表达含量增高,同时摄碘率增高,而在甲状腺滤泡状癌细胞系RO82-W-1中,抑制BRAF基因后,其NIS,THSR以及摄碘率却没有明显变化。
结论:抑制变异的BRAF基因能够增加甲状腺乳头状癌的摄碘率以及相关基因的表达,而在表达正常BRAF基因的细胞中抑制其表达,则不能相应的增加其摄碘率以及相关基因的表达,可以说明BRAF基因的变异,以及BRAF蛋白的表达增多,能够导致甲状腺癌细胞摄碘率的降低,使着甲状腺癌向去分化的过程进展。
Objective: We research the effect of mutation BRAF gene and BRAF-wt to iodine uptake and relative gene in the thyroid carcinoma cell individually.
Methods: In the papillary thyroid carcinoma cell line K1 which express mutation BRAF, we knockdown BRAF gene by the special shRNA, then observe the change of capacity of iodine uptake with radiative I125 and the expressin of relative gene and protein of thyroid stimulating hormone receptor (TSHR) and Sodium iodide symporter (NIS), and knockdown BRAF gene in the follicular thyroid cancer which express BRAF-wt,we determine the expression of NIS,TSHR and capacity of iodine uptake with radiative I125.
Result: In the investigation,we found the phenomenon that the capacity of iodine uptake increases while BRAF DNA and protein diminishs in papillary thyroid carcinoma which expresses the mutatant BRAF,meanwhile the expression of NIS and TSHR increase. However, in follicular thyroid cancer RO82-W-1, after inhibition the expression of BRAF, we could not find the change of expression of NIS,TSHR and capacity of iodine uptake with radiative I125.
Conclusion: The mutation of BRAF gene could increase the iodine uptake and relative gene in papillary thyroid cancer which express the mutation BRAF, but in follicular thyroid cancer, inhibition BRAF could not influence NIS, TSHR and iodine uptake. The research indicates that mutation BRAF gene induce the loss of capacity of iodine uptake and promote the progress of didifferentiation of thyroid cancer. Mutation BRAF is patient to be a new target of genetic therapy to the thyriod cancer which is insensitive to radiative therapy.
引文
[1] Jemal A, Murray T,Ward E, et al. Cancer statistics, 2005. CA CancerJClin 2005,55:10-30.
[2] BRAF mutatiom in papillary thyroid carcinoma, Natl Cancer Inst,2003,95:625- 627.
[3] High prevalence of BRAF mutation in thyroid cancer. Genetic evedence four constirutive activation of the RET/PTC - RAS - BRAF signaling pathway in papillary throid carcinoma ,Cancer Res,2003,63;1454- 1457.
[4] Grant BD,Hemmer W,Tsigelny I,et al. Analyses of mutations in the glycine - rich loop of cAMP - dependent protein kinase. Biochemistry,1998,37(21):7708- 15.
[5] BRAF Mutations in Papillary Thyroid Carcinomas Inhibit Genes Involved in Iodine Metabolism. The Journal of Clinical Endocrinology & Metabolism 92(7):2840–2843
[6] Suppression of BRAF/MEK/MAP Kinase Pathway Restores Expression of Iodide-MetabolizingGe nes inThyroid Cells Expressingt heV600E BRAFMutant, Clin Cancer Res 2007;1349 13(4) February 15, 2007
[7]Braf mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-Ras-Braf pathway in papillary thyroid carcinogenesis.
[8] Xing M. Braf mutation in thyroid cancer. Endocr Relat Cancer. 2005 Jun; 12(2):245-62.
[9] The oncogene BRAFV600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/Ix targeting to the membrane, Endocrine-Related Cancer (2006) 13 257–269
[10] Adenovirus mediated transfer of the thyroid Na + / I- symporter nene into tumors for a tar2 neted radiotherapy. Cancer Res, 2000, 60: 3484
[11] Radioisotope concen2 trator gene therapy using the sodium / iodide symporter. Cancer Res, 1999, 59 (3) : 661 - 668.
[12] Suppression of BRAF(A599E) in human melanoma abrogates transformation . Cancer Res,2003,63,5198-5202
[1] Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward,et al. Cancer Statistics, 2008. CA Cancer J Clin. 2008; 58; 71-96.
[2] Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998 Jan 29; 338(5):297-306.
[3] Hiltzik D,Carlson DL,Tuttle RM,et al. Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients. Cancer. 2006 Mar 15; 106(6):1286-95.
[4] Nikiforov Y.E. Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas Endocrine Pathology 2004 15:4 (319-327)
[5] Fukushima T,Suzuki S,Mashiko M,et al. Braf mutations in papillary carcinomas of the thyroid. Oncogene ,2003 ,22 :645526457.
[6] Namba H ,Nakashima M,Hayashida N ,et al . Clinical implication of hot spot Braf mutationV599E in papillary thyroid cancers. J Clin En2docrinol Metab,2003 ,88 :439324397.
[7] Xu X,Quiros RM,Gattuso P,et al . High prevalence of Braf gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res,2003,63 : 456124567.
[8] Begum S,Rosenbaum E,Henrique R,et al . Braf mutations in an aplastic thyroid carcinoma : implications for tumor origin,diagnosis and treatment . Mod Pathol ,2004,17 :135921363.
[9] Kumagai A,Namba H,Saenko VA,et al . Low frequency of BrafT1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab,2004,89 :428024284.
[10]Braf mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-Ras-Braf pathway in papillary thyroid carcinogenesis.
[11] Xing M. Braf mutation in thyroid cancer. Endocr Relat Cancer. 2005 Jun; 12(2):245-62.
[12] Kim KH,Suh KS,KangDW,et al. Mutations of the Braf gene in papillary thyroid carcinoma and in Hashimoto’s thyroiditis. Pathol Int. 2005 Sep; 55(9):540-5.
[13] Trovisco V,Vieira de Castro I,Soares P,et al. Braf mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004 Feb; 202(2):247-51.
[14] Xing M,Tufano R,Tufano A,et al. Detection of Braf mutation on fine needleasp irationbiopsy speciments: a new diagnosis tool for papillary thyroid cancer. J Clin Endocrineol Metab,2004; 89: 2867
[15] Bargonetti J,Manfredi JJ. Multiple roles of the tumor suppressor p53. CurrOpin Oncol. 2002 Jan; 14(1):86-91
[16] Kodama T,Fujimoto Y,Obara T,et al. Histochemical demonstration of thyroxine,triiodothyronine,and thyroglobulin in the primary lesion of thyroid carcinoma,and its predictability for radioiodine uptake by metastatic lesions. World J Surg. 1988 Aug; 12(4):439-44.
[17] Takeshita Y,Takamura T,Minato H,et al. Transformation of p53-positive papillary thyroid carcinoma to anaplastic carcinoma of the liver following postoperative radioactive iodine-131 therapy. Intern Med. 2008; 47(19):1709-12.
[18] A novel panel of antibodies that segregates immunocytochemically poorly differentiated carcinoma from undifferentiated carcinoma of the thyroid gland. Pilotti S,Collini P,Del Bo R,Cattoretti G,Pierotti M.A. and Rilke F. American Journal of Surgical Pathology 1994 18:10 (1054-1064)
[19] Nuclear p53 immunoreactivity in papillary thyroid cancers is associated with two established indicators of poor prognosis. Gerasimov G,Bronstein M,Troshina K,Alexandrova G,Dedov I,Jennings T, Kallakury B,Izquierdo R,Boguniewicz A,Figge H,Robinson L,Breese K,Ross J.S. and Figge J. Experimental and Molecular Pathology 1995 62:1 (52-62)
[20] Simon D., Goretzki P.E., Gorelev V., Ebling B., Reishaus E., Lyons J., Haubruck H., Roher H.D. and Herrmann M.E. Significance of p53 in human thyroid tumors. World Journal of Surgery 1994 18:4 (535-541)
[21] Zou M., Shi Y. and Farid N.R. p53 mutations in all stages of thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 1993 77:4 (1054-1058)
[22] Dobashi Y., Sugimura H., Sakamoto A, Mernyei M., MoriM.,Oyama T. and Machinami R. Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagnostic Molecular Pathology 1994 196 : 127.
[23] Motoi N,Sakamoto A,Yamochi T,et al . Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract,2000,196 : 127.
[24] Liu RT ,Hou CY,You HL ,et al . Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid,2004 ,14 :6162621.
[25] Volante M,Rapa I,Gandhi M,Bussolati G,Giachino D,Papotti M. Ras mutations are the predominant molecular alteration in poorly differentiated thyroid carcinomas and bear prognostic impact. J Clin Endocrinol Metab. 2009Dec;94(12):4735-41. Epub 2009 Oct 16.
[26] Palos-Paz F,Perez-Guerra O,Cameselle-Teijeiro J,Rueda-Chimeno C, Barreiro-Morandeira FEur J Endocrinol. Prevalence of mutations in TSHR, GNAS,PRKAR1A and Ras genes in a large series of toxic thyroid adenomas from Galicia,an iodine-deficient area in NW Spain. 2008 Nov;159(5):623-31.
[27] TakahashiM . 1988 Structure and expression of the ret transforming gene. IARC Sci Publ 189–197
[28] Takahashi M,Ritz J. Cooper GM 1985 Activation of a novel human transforming gene RETby DNA rearrangement. Cell 42:581–588
[29] Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA. A new oncogene in human thyroid papillary carcinomas and their lymphnodal metastases. Nature 328:170–172
[30] Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I,Pierotti MA. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563
[31] Santoro M, Melillo RM, Grieco M, Berlingieri MT. The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth Differ 4:77–84
[32] Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375–378
[33] Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli G. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–1826
[34] Powell Jr DJ, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 58: 5523–5528
[35] Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, VecchioG,Ryan AJ, Fontanini G, Fusco A. an orally available inhibitor of KDR tyrosine kinase activity,efficiently blocks oncogenic RET kinases. Cancer Res 62:7284–7290
[36] Carlomagno F, Vitagliano D, Guida T, Napolitano M, Vecchio G, Fusco A,Gazit A. The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res 62:1077–1082
[2] BRAF mutatiom in papillary thyroid carcinoma, Natl Cancer Inst,2003,95:625- 627.
[3] High prevalence of BRAF mutation in thyroid cancer. Genetic evedence four constirutive activation of the RET/PTC - RAS - BRAF signaling pathway in papillary throid carcinoma ,Cancer Res,2003,63;1454- 1457.
[4] Grant BD,Hemmer W,Tsigelny I,et al. Analyses of mutations in the glycine - rich loop of cAMP - dependent protein kinase. Biochemistry,1998,37(21):7708- 15.
[5] BRAF Mutations in Papillary Thyroid Carcinomas Inhibit Genes Involved in Iodine Metabolism. The Journal of Clinical Endocrinology & Metabolism 92(7):2840–2843
[6] Suppression of BRAF/MEK/MAP Kinase Pathway Restores Expression of Iodide-MetabolizingGe nes inThyroid Cells Expressingt heV600E BRAFMutant, Clin Cancer Res 2007;1349 13(4) February 15, 2007
[7]Braf mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-Ras-Braf pathway in papillary thyroid carcinogenesis.
[8] Xing M. Braf mutation in thyroid cancer. Endocr Relat Cancer. 2005 Jun; 12(2):245-62.
[9] The oncogene BRAFV600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/Ix targeting to the membrane, Endocrine-Related Cancer (2006) 13 257–269
[10] Adenovirus mediated transfer of the thyroid Na + / I- symporter nene into tumors for a tar2 neted radiotherapy. Cancer Res, 2000, 60: 3484
[11] Radioisotope concen2 trator gene therapy using the sodium / iodide symporter. Cancer Res, 1999, 59 (3) : 661 - 668.
[12] Suppression of BRAF(A599E) in human melanoma abrogates transformation . Cancer Res,2003,63,5198-5202
[1] Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward,et al. Cancer Statistics, 2008. CA Cancer J Clin. 2008; 58; 71-96.
[2] Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998 Jan 29; 338(5):297-306.
[3] Hiltzik D,Carlson DL,Tuttle RM,et al. Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients. Cancer. 2006 Mar 15; 106(6):1286-95.
[4] Nikiforov Y.E. Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas Endocrine Pathology 2004 15:4 (319-327)
[5] Fukushima T,Suzuki S,Mashiko M,et al. Braf mutations in papillary carcinomas of the thyroid. Oncogene ,2003 ,22 :645526457.
[6] Namba H ,Nakashima M,Hayashida N ,et al . Clinical implication of hot spot Braf mutationV599E in papillary thyroid cancers. J Clin En2docrinol Metab,2003 ,88 :439324397.
[7] Xu X,Quiros RM,Gattuso P,et al . High prevalence of Braf gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res,2003,63 : 456124567.
[8] Begum S,Rosenbaum E,Henrique R,et al . Braf mutations in an aplastic thyroid carcinoma : implications for tumor origin,diagnosis and treatment . Mod Pathol ,2004,17 :135921363.
[9] Kumagai A,Namba H,Saenko VA,et al . Low frequency of BrafT1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metab,2004,89 :428024284.
[10]Braf mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-Ras-Braf pathway in papillary thyroid carcinogenesis.
[11] Xing M. Braf mutation in thyroid cancer. Endocr Relat Cancer. 2005 Jun; 12(2):245-62.
[12] Kim KH,Suh KS,KangDW,et al. Mutations of the Braf gene in papillary thyroid carcinoma and in Hashimoto’s thyroiditis. Pathol Int. 2005 Sep; 55(9):540-5.
[13] Trovisco V,Vieira de Castro I,Soares P,et al. Braf mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol. 2004 Feb; 202(2):247-51.
[14] Xing M,Tufano R,Tufano A,et al. Detection of Braf mutation on fine needleasp irationbiopsy speciments: a new diagnosis tool for papillary thyroid cancer. J Clin Endocrineol Metab,2004; 89: 2867
[15] Bargonetti J,Manfredi JJ. Multiple roles of the tumor suppressor p53. CurrOpin Oncol. 2002 Jan; 14(1):86-91
[16] Kodama T,Fujimoto Y,Obara T,et al. Histochemical demonstration of thyroxine,triiodothyronine,and thyroglobulin in the primary lesion of thyroid carcinoma,and its predictability for radioiodine uptake by metastatic lesions. World J Surg. 1988 Aug; 12(4):439-44.
[17] Takeshita Y,Takamura T,Minato H,et al. Transformation of p53-positive papillary thyroid carcinoma to anaplastic carcinoma of the liver following postoperative radioactive iodine-131 therapy. Intern Med. 2008; 47(19):1709-12.
[18] A novel panel of antibodies that segregates immunocytochemically poorly differentiated carcinoma from undifferentiated carcinoma of the thyroid gland. Pilotti S,Collini P,Del Bo R,Cattoretti G,Pierotti M.A. and Rilke F. American Journal of Surgical Pathology 1994 18:10 (1054-1064)
[19] Nuclear p53 immunoreactivity in papillary thyroid cancers is associated with two established indicators of poor prognosis. Gerasimov G,Bronstein M,Troshina K,Alexandrova G,Dedov I,Jennings T, Kallakury B,Izquierdo R,Boguniewicz A,Figge H,Robinson L,Breese K,Ross J.S. and Figge J. Experimental and Molecular Pathology 1995 62:1 (52-62)
[20] Simon D., Goretzki P.E., Gorelev V., Ebling B., Reishaus E., Lyons J., Haubruck H., Roher H.D. and Herrmann M.E. Significance of p53 in human thyroid tumors. World Journal of Surgery 1994 18:4 (535-541)
[21] Zou M., Shi Y. and Farid N.R. p53 mutations in all stages of thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 1993 77:4 (1054-1058)
[22] Dobashi Y., Sugimura H., Sakamoto A, Mernyei M., MoriM.,Oyama T. and Machinami R. Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagnostic Molecular Pathology 1994 196 : 127.
[23] Motoi N,Sakamoto A,Yamochi T,et al . Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract,2000,196 : 127.
[24] Liu RT ,Hou CY,You HL ,et al . Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid,2004 ,14 :6162621.
[25] Volante M,Rapa I,Gandhi M,Bussolati G,Giachino D,Papotti M. Ras mutations are the predominant molecular alteration in poorly differentiated thyroid carcinomas and bear prognostic impact. J Clin Endocrinol Metab. 2009Dec;94(12):4735-41. Epub 2009 Oct 16.
[26] Palos-Paz F,Perez-Guerra O,Cameselle-Teijeiro J,Rueda-Chimeno C, Barreiro-Morandeira FEur J Endocrinol. Prevalence of mutations in TSHR, GNAS,PRKAR1A and Ras genes in a large series of toxic thyroid adenomas from Galicia,an iodine-deficient area in NW Spain. 2008 Nov;159(5):623-31.
[27] TakahashiM . 1988 Structure and expression of the ret transforming gene. IARC Sci Publ 189–197
[28] Takahashi M,Ritz J. Cooper GM 1985 Activation of a novel human transforming gene RETby DNA rearrangement. Cell 42:581–588
[29] Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA. A new oncogene in human thyroid papillary carcinomas and their lymphnodal metastases. Nature 328:170–172
[30] Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I,Pierotti MA. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563
[31] Santoro M, Melillo RM, Grieco M, Berlingieri MT. The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth Differ 4:77–84
[32] Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho JY. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375–378
[33] Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli G. Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–1826
[34] Powell Jr DJ, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M. The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 58: 5523–5528
[35] Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, VecchioG,Ryan AJ, Fontanini G, Fusco A. an orally available inhibitor of KDR tyrosine kinase activity,efficiently blocks oncogenic RET kinases. Cancer Res 62:7284–7290
[36] Carlomagno F, Vitagliano D, Guida T, Napolitano M, Vecchio G, Fusco A,Gazit A. The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer Res 62:1077–1082