PATZ1 knockdown enhances malignant phenotype in thyroid epithelial follicular cells and thyroid cancer cells.
PATZ1 knockdown enhances malignant phenotype in thyroid epithelial follicular cells and thyroid cancer cells.
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DOI：
10.18632/oncotarget.19787
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发表时间：
2017-10-10
期刊：
影响因子：
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通讯作者：
Ito KI
中科院分区：
文献类型：
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作者：
Iesato A;Nakamura T;Izumi H;Uehara T;Ito KI
本研究旨在探讨PATZ1在甲状腺癌发生和去分化中的作用。临床标本免疫组织化学结果显示，PATZ1在所有正常甲状腺组织和腺瘤性甲状腺肿中均有核表达，但随着甲状腺癌组织分化程度的降低，PATZ1核表达逐渐减少。在永生化的正常卵泡上皮细胞系(Nthy-Ori3-1)中，通过siRNA敲除核PATZ1改变了细胞的形态，显著增加了细胞的增殖、迁移和侵袭。此外，PATZ1基因敲除后，Nthy-ori 3-1细胞尿激酶型纤溶酶原激活物(UPA)、基质金属蛋白酶(MMP2)、MMP9和MMP11的表达增加。当PATZ1在分化型甲状腺癌(DTC)细胞系(TPC-1和FTC-133)中被沉默时，细胞的增殖和运动能力以及uPA和MMPs的表达显著增加。外源性PATZ1的强制表达降低了ATC细胞系(ACT-1和FRO)的增殖、细胞活力以及uPA和MMPs的表达。在甲状腺癌细胞系中，PATZ1作为肿瘤抑制因子发挥作用，与P53的状态无关。此外，无论P53状态如何，ATC中PATZ1核阳性肿瘤的比例均显著降低。我们的研究表明，PATZ1基因敲除增强了甲状腺滤泡上皮细胞和甲状腺癌细胞的恶性表型，提示PATZ1在甲状腺滤泡上皮细胞中具有肿瘤抑制作用，并参与了甲状腺癌的去分化过程。
This study was designed to examine the involvement of PATZ1 in carcinogenesis and dedifferentiation of thyroid cancer. Immunohistochemistry on clinical specimens indicated nuclear PATZ1 expression in all normal thyroid glands and adenomatous goiter, while nuclear PATZ1 expression decreased along with the dedifferentiation of thyroid cancer. Knockdown of nuclear PATZ1 by siRNA in an immortalized normal follicular epithelial cell line (Nthy-ori 3-1) altered cellular morphology and significantly increased cell proliferation, migration, and invasion. In addition, the expression of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP) 2, MMP9, and MMP11 was increased by PATZ1 knockdown in Nthy-ori 3-1 cells. When PATZ1 was silenced in differentiated thyroid cancer (DTC) cell lines (TPC-1 and FTC-133), proliferation, cellular motility, and expression of uPA and MMPs were significantly increased. Forced expression of exogenous PATZ1 decreased proliferation, cellular motility, and the expression of uPA and MMPs in ATC cell lines (ACT-1 and FRO). In thyroid cancer cell lines, PATZ1 functioned as a tumor suppressor regardless of p53 status. Moreover, the ratio of nuclear PATZ1 positive tumors was significantly decreased in ATC irrespective of p53 status. Our study demonstrates that PATZ1 knockdown enhances malignant phenotype both in thyroid follicular epithelial cells and thyroid cancer cells, suggesting that PATZ1 functions as a tumor suppressor in thyroid follicular epithelial cells and is involved in the dedifferentiation of thyroid cancer.