DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells
DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells
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DOI：
10.1530/erc-12-0078
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发表时间：
2013-02-01
影响因子：
3.9
通讯作者：
Borrello, Maria Grazia
中科院分区：
文献类型：
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作者：
Degl'Innocenti, Debora;Romeo, Paola;Borrello, Maria Grazia
来源于滤泡细胞的甲状腺癌包括乳头状甲状腺癌（PTC）、滤泡状甲状腺癌、低分化甲状腺癌（PDTC）和未分化间变性甲状腺癌（ATC）。PTC是最常见的甲状腺癌组织类型，与产生RET/PTC和TRK癌基因的基因重排以及BRAF-V600 E和RAS基因突变相关。这最后两种遗传病变也存在于一部分PDTC中。ERK 1/2通路位于PTC中激活的已知癌基因下游，在甲状腺癌发生中起核心作用。在这项研究中，我们证明了BRAF-V600 E，RET/PTC和TRK癌基因上调ERK 1/2途径的衰减剂细胞质双相磷酸酶DUSP 6/MKP 3在甲状腺细胞。我们还显示在所有分析的PTC细胞系中在mRNA和蛋白质水平上DUSP 6过表达。此外，在表达谱数据集和通过实时RT-PCR分析的患者手术样品中，与正常甲状腺组织相比，PTC和PDTC中的DUSP 6 mRNA显著更高。免疫组化和western blot分析显示，DUSP 6在大多数PTC和PDTC手术样本中也在蛋白水平上过表达，但在ATC中没有，并显示出与ERK 1/2通路激活正相关的趋势。最后，DUSP 6沉默降低了四种PTC细胞系的肿瘤特性，从而表明DUSP 6可能在甲状腺癌发生中具有促肿瘤作用。
Thyroid carcinomas derived from follicular cells comprise papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC) and undifferentiated anaplastic thyroid carcinoma (ATC). PTC, the most frequent thyroid carcinoma histotype, is associated with gene rearrangements that generate RET/PTC and TRK oncogenes and with BRAF-V600E and RAS gene mutations. These last two genetic lesions are also present in a fraction of PDTCs. The ERK1/2 pathway, downstream of the known oncogenes activated in PTC, has a central role in thyroid carcinogenesis. In this study, we demonstrate that the BRAF-V600E, RET/PTC, and TRK oncogenes upregulate the ERK1/2 pathway's attenuator cytoplasmic dual-phase phosphatase DUSP6/MKP3 in thyroid cells. We also show DUSP6 overexpression at the mRNA and protein levels in all the analysed PTC cell lines. Furthermore, DUSP6 mRNA was significantly higher in PTC and PDTC in comparison with normal thyroid tissues both in expression profile datasets and in patients' surgical samples analysed by real-time RT-PCR. Immunohistochemical and western blot analyses showed that DUSP6 was also overexpressed at the protein level in most PTC and PDTC surgical samples tested, but not in ATC, and revealed a positive correlation trend with ERK1/2 pathway activation. Finally, DUSP6 silencing reduced the neoplastic properties of four PTC cell lines, thus suggesting that DUSP6 may have a pro-tumorigenic role in thyroid carcinogenesis.