The role of SET/I2PP2A in canine mammary tumors.
The role of SET/I2PP2A in canine mammary tumors.
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DOI：
10.1038/s41598-017-04291-7
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发表时间：
2017-06-27
影响因子：
4.6
通讯作者：
Sato K
中科院分区：
文献类型：
--
作者：
Kake S;Tsuji S;Enjoji S;Hanasaki S;Hayase H;Yabe R;Tanaka Y;Nakagawa T;Liu HP;Chang SC;Usui T;Ohama T;Sato K
犬乳腺肿瘤是母犬最常见的肿瘤，作为人类乳腺癌的翻译模型已引起人们的广泛关注。丝氨酸/苏氨酸蛋白磷酸酶2A(PP2A)是一种重要的肿瘤抑制因子，其内源性抑制蛋白SET/I2PP2A直接与PP2A结合并抑制其磷酸酶活性。在这里，我们研究了SET在犬乳腺肿瘤发生发展中的作用，以及在肿瘤对现有治疗方法的敏感性中的作用。与配对正常组织相比，晚期犬乳腺肿瘤组织中SET蛋白水平升高。SET在犬乳腺肿瘤细胞系CIP-m中的表达下调导致PP2A活性增加，细胞增殖、克隆形成和体内肿瘤生长减少。我们观察到SET基因敲除对mTOR、β-连环蛋白和核因子κB信号的抑制。SET基因敲除降低了CIP-m细胞对阿霉素的敏感性，而CIP-m细胞的SET基因敲除不影响对4-OH-他莫昔芬、卡铂、硼替佐米和X射线的敏感性。这些数据表明，SET通过抑制PP2A活性、增强mTOR、β-连环蛋白和核因子κB信号，在犬乳腺肿瘤亚群的肿瘤进展中发挥重要作用。
Canine mammary tumor is the most common neoplasm in female dogs, and it has generated considerable attention as a translational model for human breast cancer. Ser/Thr protein phosphatase 2A (PP2A) plays a critical role as a tumor suppressor, and SET/I2PP2A, the endogenous inhibitory protein of PP2A, binds directly to PP2A and suppresses its phosphatase activity. Here, we investigated the role of SET in the tumorigenic growth in canine mammary tumor as well as in the sensitivity of tumors to existing therapeutics. Elevated protein levels of SET were observed in advanced-stage of canine mammary tumor tissues of dogs compared with paired normal tissues. Knockdown of SET expression in a canine mammary tumor cell line CIP-m led to increased PP2A activity and decreased cell proliferation, colony formation, and in vivo tumor growth. We observed suppression of mTOR, β-catenin, and NFκB signaling by SET knockdown. The sensitivity of CIP-m cells to doxorubicin was decreased by SET knockdown, while SET knockdown in CIP-m cells did not affect sensitivity to 4-OH-tamoxifen, carboplatin, bortezomib, and X-ray radiation. These data suggest that SET plays important roles in the tumor progression of a subset of canine mammary tumor by suppressing PP2A activity and enhancing mTOR, β-catenin, and NFκB signaling.