AG490对甲状腺髓样癌TT细胞放射敏感性的影响
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摘要
为了研究AG490对甲状腺髓样癌TT细胞放射敏感性,本研究选择甲状腺髓样癌TT细胞作为研究对象,并采用不同浓度AG490 (0, 25μmol/L, 50μmol/L, 100μmol/L)处理细胞,利用MTT法、流式细胞术和克隆形成实验分别对细胞增殖、凋亡及放射敏感性进行检测,并采用Western blotting法检测各组JAK2、p-STAT3、Bcl-2、Bax蛋白表达。结果表明,与A组相比,B、C、D组的抑制增殖作用增强,呈浓度和时间依赖性;随着AG490药物浓度的增加凋亡率逐渐增加;与A组相比,C组细胞存活分数显著降低;JAK2、p-STAT3和Bcl-2的蛋白表达量随着药物浓度的升高而逐渐降低,Bax蛋白表达量随着药物浓度的升高而逐渐增加。AG490对甲状腺髓样癌TT细胞增殖有抑制作用,可促进细胞凋亡,提高放射敏感性。
In order to study the effects of AG490 on the radiosensitivity of medullary thyroid carcinoma TT cells,we chose medullary thyroid carcinoma TT cell as the research object. TT cells were treated with different concentrations of AG490(0, 25 μmol/L, 50 μmol/L, 100 μmol/L). Cell proliferation, apoptosis and radiosensitivity were respectively detected by MTT method, flow cytometry and clone formation assay. The protein expressions of JAK2, p-STAT3, Bcl-2 and Bax in each group were detected by Western blotting.The results showed that compared with group A, the inhibition effects on proliferation of thyroid TT cells in groups B, C, D significantly decreased in a concentration and time dependent manner, and the apoptosis rate of TT cells gradually increased along with the increasing concentrations of AG490. There was a significant decrease in cell survival fraction in group C compared with group A. The protein expressions of JAK2, p-STAT3 and Bcl-2 gradually reduced with the increasing concentration of AG490, while the expression of Bax increased with the increasing concentration of AG490. AG490 could inhibit the proliferation, increase the apoptosis rate and enhance the radiosensitivity of human medullary thyroid carcinoma TT cells.
In order to study the effects of AG490 on the radiosensitivity of medullary thyroid carcinoma TT cells,we chose medullary thyroid carcinoma TT cell as the research object. TT cells were treated with different concentrations of AG490(0, 25 μmol/L, 50 μmol/L, 100 μmol/L). Cell proliferation, apoptosis and radiosensitivity were respectively detected by MTT method, flow cytometry and clone formation assay. The protein expressions of JAK2, p-STAT3, Bcl-2 and Bax in each group were detected by Western blotting.The results showed that compared with group A, the inhibition effects on proliferation of thyroid TT cells in groups B, C, D significantly decreased in a concentration and time dependent manner, and the apoptosis rate of TT cells gradually increased along with the increasing concentrations of AG490. There was a significant decrease in cell survival fraction in group C compared with group A. The protein expressions of JAK2, p-STAT3 and Bcl-2 gradually reduced with the increasing concentration of AG490, while the expression of Bax increased with the increasing concentration of AG490. AG490 could inhibit the proliferation, increase the apoptosis rate and enhance the radiosensitivity of human medullary thyroid carcinoma TT cells.
引文
Bao S.D.,Pang P.,Zang L.,Chen K.,Gu W.J.,Yang G.Q.,Du J.,Tian W.,Luo Y.K.,LüZ.H.,Dou J.T.,and Mu Y.M.,2016,Predictive value of sonographic features in preoperative evaluation of medullary thyroid carcinoma,Zhonghua Yixue Zazhi,96(31):2482-2486
Barmpari M.E.,Savvidis C.,Dede A.D.,Markogiannakis H.,Dikoglou C.,Xekouki P.,Stratakis C.A.,Manouras A.,and Malaktari-Skarantavou S.,2016,Adrenal malignant melanoma masquerading as a pheochromocytoma in a patient with a history of a multifocal papillary and medullary thyroid carcinoma,Hormones(Athens),15(2):283-290
Hassan A.,Siddiqui M.,and Jahangir S.,2016,A rare case of medullary carcinoma thyroid metastasizing to bilateral breast parenchyma,Nuclear Medicine Review Central and Eastern Europe,19(B):17-19
He H.J.,Chen E.F.,and Lei L.,2015,Association of tumorigenesis with the related gene mutation,Jiyin Zuxue Yu Yingyong Shengwuxue(Genomics and Applied Biology),34(1):208-214(贺红娟,陈尔飞,雷蕾,2015,肿瘤发生与相关基因突变的关联,基因组学与应用生物学,34(1):208-214)
Herac M.,Niederle B.,Raderer M.,Krebs M.,Kaserer K.,and Koperek O.,2016,Expression of somatostatin receptor 2Ain medullary thyroid carcinoma is associated with lymph node metastasis,APMIS,124(10):839-845
Jiang K.,Lei J.,Chen W.,Gong Y.,Luo H.,Li Z.,Gong R.,and Zhu J.,2016,Association of the preoperativ e neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios with lymph node metastasis and recurrence in patients with medullary thyroid carcinoma,Medicine(Baltimore),95(40):e5079
Lai X.,Liu M.,Xia Y.,Wang L.,Bi Y.,Li X.,Zhang B.,Yang M.,Dai Q.,and Jiang Y.,2016,Hypervascularity is more frequent in medullary thyroid carcinoma:Compared with papil lary thyroid carcinoma,Medicine(Baltimore),95(49):e5502
Luo S.,Li Z.,Xu M.,Zhang Q.,Qu Y.,and Lu L.,2015,Reversal of liver fibrosis through AG490 inhibitor-mediated inhibition of the TGFbeta1-STAT3 pathway,Zhonghua Gan Zang Bing Za Zhi,23(12):939-943
Maia A.L.,Wajner S.M.,and Vargas C.V.,2017,Advances and controversies in the management of medullary thyroid carcinoma,Curr.Opin.Oncol.,29(1):25-32
Now H.,and Yoo J.Y.,2016,AG490 and PF431396 sensitive tyrosine kinase control the population heterogeneity of basal STAT1 activity in Ube1l deficient cells,PLoS One,11(7):e0159453
Segura D.,Dupuis C.,Chabre O.,Piolat C.,Durand C.,and Plantaz D.,2016,Metastatic medullary thyroid carcinoma in a child with multiple endocrine neoplasia 2B.Efficiency of medium-term treatment with vandetanib without thyroid surgery,Arch.Pediatr.,23(8):840-844
Simoes-Pereira J.,Bugalho M.J.,Limbert E.,and Leite V.,2016,Retrospective analysis of 140 cases of medullary thyroid carcinoma followed-up in a single institution,Oncol.Lett.,11(6):3870-3874
Wang G.,Zhang J.,Dui D.,Ren H.,and Liu J.,2016,High mobility group box 1 induces the activation of the janus kinase2 and signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway in pancreatic acinar cells in rats,while AG490 and rapamycin inhibit their activation,Bosnian Journal of Basic Medical Sciences,16(4):307-312
Yamasaki M.,Sato Y.,Nomura T.,Sato F.,Uchino S.,and Mimata H.,2017,Composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2B:a case report,Asian J.Endosc.Surg.,10(1):66-69
Zhang M.,Nong G.,Jiang M.,and Zhan W.,2016,Lipid derivative of benzylidene malononitrile AG490 attenuates airway inflammation of mice with neutrophilic asthma,Chinese Journal of Cellular and Molecular Immunology,32(6):730-733
Barmpari M.E.,Savvidis C.,Dede A.D.,Markogiannakis H.,Dikoglou C.,Xekouki P.,Stratakis C.A.,Manouras A.,and Malaktari-Skarantavou S.,2016,Adrenal malignant melanoma masquerading as a pheochromocytoma in a patient with a history of a multifocal papillary and medullary thyroid carcinoma,Hormones(Athens),15(2):283-290
Hassan A.,Siddiqui M.,and Jahangir S.,2016,A rare case of medullary carcinoma thyroid metastasizing to bilateral breast parenchyma,Nuclear Medicine Review Central and Eastern Europe,19(B):17-19
He H.J.,Chen E.F.,and Lei L.,2015,Association of tumorigenesis with the related gene mutation,Jiyin Zuxue Yu Yingyong Shengwuxue(Genomics and Applied Biology),34(1):208-214(贺红娟,陈尔飞,雷蕾,2015,肿瘤发生与相关基因突变的关联,基因组学与应用生物学,34(1):208-214)
Herac M.,Niederle B.,Raderer M.,Krebs M.,Kaserer K.,and Koperek O.,2016,Expression of somatostatin receptor 2Ain medullary thyroid carcinoma is associated with lymph node metastasis,APMIS,124(10):839-845
Jiang K.,Lei J.,Chen W.,Gong Y.,Luo H.,Li Z.,Gong R.,and Zhu J.,2016,Association of the preoperativ e neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios with lymph node metastasis and recurrence in patients with medullary thyroid carcinoma,Medicine(Baltimore),95(40):e5079
Lai X.,Liu M.,Xia Y.,Wang L.,Bi Y.,Li X.,Zhang B.,Yang M.,Dai Q.,and Jiang Y.,2016,Hypervascularity is more frequent in medullary thyroid carcinoma:Compared with papil lary thyroid carcinoma,Medicine(Baltimore),95(49):e5502
Luo S.,Li Z.,Xu M.,Zhang Q.,Qu Y.,and Lu L.,2015,Reversal of liver fibrosis through AG490 inhibitor-mediated inhibition of the TGFbeta1-STAT3 pathway,Zhonghua Gan Zang Bing Za Zhi,23(12):939-943
Maia A.L.,Wajner S.M.,and Vargas C.V.,2017,Advances and controversies in the management of medullary thyroid carcinoma,Curr.Opin.Oncol.,29(1):25-32
Now H.,and Yoo J.Y.,2016,AG490 and PF431396 sensitive tyrosine kinase control the population heterogeneity of basal STAT1 activity in Ube1l deficient cells,PLoS One,11(7):e0159453
Segura D.,Dupuis C.,Chabre O.,Piolat C.,Durand C.,and Plantaz D.,2016,Metastatic medullary thyroid carcinoma in a child with multiple endocrine neoplasia 2B.Efficiency of medium-term treatment with vandetanib without thyroid surgery,Arch.Pediatr.,23(8):840-844
Simoes-Pereira J.,Bugalho M.J.,Limbert E.,and Leite V.,2016,Retrospective analysis of 140 cases of medullary thyroid carcinoma followed-up in a single institution,Oncol.Lett.,11(6):3870-3874
Wang G.,Zhang J.,Dui D.,Ren H.,and Liu J.,2016,High mobility group box 1 induces the activation of the janus kinase2 and signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway in pancreatic acinar cells in rats,while AG490 and rapamycin inhibit their activation,Bosnian Journal of Basic Medical Sciences,16(4):307-312
Yamasaki M.,Sato Y.,Nomura T.,Sato F.,Uchino S.,and Mimata H.,2017,Composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2B:a case report,Asian J.Endosc.Surg.,10(1):66-69
Zhang M.,Nong G.,Jiang M.,and Zhan W.,2016,Lipid derivative of benzylidene malononitrile AG490 attenuates airway inflammation of mice with neutrophilic asthma,Chinese Journal of Cellular and Molecular Immunology,32(6):730-733