Zhao Zhiyan, Herman James G, Brock Malcolm V, Sheng Jindong, Zhang Meiying, Liu Baoguo, Guo Mingzhou
The Department of Head & Neck Surgery, Peking University Cancer Hospital and Institute, #52 Fucheng Road, Beijing 100036, China; The Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Bunting-Blaustein Cancer Research Building, Room 543, 1650 Orleans Street, Baltimore, Maryland 21231, United States of America.
PLoS One. 2014 Nov 6;9(11):e112336. doi: 10.1371/journal.pone.0112336. eCollection 2014.
Thyroid cancer is the most common endocrine malignant disease and the incidence is increasing. DACT2 was found frequently methylated in human lung cancer and hepatocellular carcinoma. To explore the epigenetic change and the role of DACT2 in thyroid cancer, 7 thyroid cancer cell lines, 10 cases of non-cancerous thyroid tissue samples and 99 cases of primary thyroid cancer samples were involved in this study. DACT2 was expressed and unmethylated in K1, SW579, FTC-133, TT, W3 and 8505C cell lines. Loss of expression and complete methylation was found in TPC-1 cells. Restoration of DACT2 expression was induced by 5-aza-2'deoxycytidine treatment. It demonstrates that the expression of DACT2 was regulated by promoter region methylation. In human primary papillary thyroid cancer, 64.6% (64/99) was methylated and methylation of DACT2 was related to lymph node metastasis (p<0.01). Re-expression of DACT2 suppresses cell proliferation, invasion and migration in TPC-1 cells. The activity of TCF/LEF was inhibited by DACT2 in wild-type or mutant β-catenin cells. The activity of TCF/LEF was increased by co-transfecting DACT2 and Dvl2 in wild-type or mutant β-catenin cells. Overexpression of wild-type β-catenin promotes cell migration and invasion in DACT2 stably expressed cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were decreased and the level of phosphorylated β-catenin (p-β-catenin) was increased after restoration of DACT2 expression in TPC-1 cells. The expression of β-catenin, c-myc, cyclinD1 and MMP-9 were increased and the level of p-β-catenin was reduced after knockdown of DACT2 in W3 and SW579 cells. These results suggest that DACT2 suppresses human papillary thyroid cancer growth and metastasis by inhibiting Wnt signaling. In conclusion, DACT2 is frequently methylated in papillary thyroid cancer. DACT2 expression was regulated by promoter region methylation. DACT2 suppresses papillary thyroid cancer proliferation and metastasis by inhibiting Wnt signaling.
甲状腺癌是最常见的内分泌恶性疾病，且发病率呈上升趋势。DACT2在人类肺癌和肝癌中经常发生甲基化。为了探究DACT2在甲状腺癌中的表观遗传变化及其作用，本研究纳入了7种甲状腺癌细胞系、10例非癌性甲状腺组织样本和99例原发性甲状腺癌样本。DACT2在K1、SW579、FTC - 133、TT、W3和8505C细胞系中表达且未发生甲基化。在TPC - 1细胞中发现表达缺失和完全甲基化。5 - 氮杂 - 2'-脱氧胞苷处理可诱导DACT2表达的恢复。这表明DACT2的表达受启动子区域甲基化调控。在人类原发性乳头状甲状腺癌中，64.6%（64/99）发生甲基化，且DACT2甲基化与淋巴结转移相关（p<0.01）。DACT2的重新表达抑制了TPC - 1细胞的增殖、侵袭和迁移。在野生型或突变型β - 连环蛋白细胞中，DACT2抑制了TCF/LEF的活性。在野生型或突变型β - 连环蛋白细胞中，共转染DACT2和Dvl2可增加TCF/LEF的活性。野生型β - 连环蛋白的过表达促进了稳定表达DACT2的细胞的迁移和侵袭。在TPC - 1细胞中恢复DACT2表达后，β - 连环蛋白、c - myc、细胞周期蛋白D1和MMP - 9的表达降低，磷酸化β - 连环蛋白（p - β - 连环蛋白）水平升高。在W3和SW579细胞中敲低DACT2后，β - 连环蛋白、c - myc、细胞周期蛋白D1和MMP - 9的表达升高，p - β - 连环蛋白水平降低。这些结果表明，DACT2通过抑制Wnt信号通路抑制人类乳头状甲状腺癌的生长和转移。总之，DACT2在乳头状甲状腺癌中经常发生甲基化。DACT2的表达受启动子区域甲基化调控。DACT2通过抑制Wnt信号通路抑制乳头状甲状腺癌的增殖和转移。
