TRIM28 multi-domain protein regulates cancer stem cell population in breast tumor development.
TRIM28 multi-domain protein regulates cancer stem cell population in breast tumor development.
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DOI：
10.18632/oncotarget.13273
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发表时间：
2017-01-03
期刊：
影响因子：
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通讯作者：
Wiznerowicz M
中科院分区：
文献类型：
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作者：
Czerwińska P;Shah PK;Tomczak K;Klimczak M;Mazurek S;Sozańska B;Biecek P;Korski K;Filas V;Mackiewicz A;Andersen JN;Wiznerowicz M
Tripartite motif-containing protein 28 (TRIM28)/ kr<s:1> pel-associated box (KRAB)-associated protein 1 （KAP1）的表达在至少14种肿瘤类型中升高，包括实体肿瘤和造血肿瘤。高水平的TRIM28与三阴性乳腺癌（TNBC）相关，其侵袭性较高，生存率较低。有趣的是，TRIM28对于维持胚胎干细胞的多能表型至关重要。根据这一发现，我们评估了TRIM28蛋白在体外和体内对乳腺癌干细胞（CSC）种群和肿瘤发生的调节中的作用。异种移植物中TRIM28表达下调导致多能性和间充质标志物表达减少，并抑制参与CSC维持复杂机制的信号通路。此外，当以有限的稀释度皮下注射时，TRIM28缺失降低了癌细胞诱导肿瘤生长的能力。我们的数据表明，TRIM28基因表达的下调降低了CSCs自我更新的能力，导致肿瘤生长显著减少。TRIM28功能丧失导致细胞周期、细胞应激反应、癌细胞代谢和氧化磷酸化抑制失调。这些机制直接调控着CSC种群的维持。我们的原始结果揭示了TRIM28在乳腺癌中调节CSC群体中的作用。这些发现可能会为新的更有效的治疗乳腺癌肿瘤的癌症干细胞铺平道路。
The expression of Tripartite motif-containing protein 28 (TRIM28)/Krüppel-associated box (KRAB)-associated protein 1 (KAP1), is elevated in at least 14 tumor types, including solid and hematopoietic tumors. High level of TRIM28 is associated with triple-negative subtype of breast cancer (TNBC), which shows higher aggressiveness and lower survival rates. Interestingly, TRIM28 is essential for maintaining the pluripotent phenotype in embryonic stem cells. Following on that finding, we evaluated the role of TRIM28 protein in the regulation of breast cancer stem cells (CSC) populations and tumorigenesis in vitro and in vivo. Downregulation of TRIM28 expression in xenografts led to deceased expression of pluripotency and mesenchymal markers, as well as inhibition of signaling pathways involved in the complex mechanism of CSC maintenance. Moreover, TRIM28 depletion reduced the ability of cancer cells to induce tumor growth when subcutaneously injected in limiting dilutions. Our data demonstrate that the downregulation of TRIM28 gene expression reduced the ability of CSCs to self-renew that resulted in significant reduction of tumor growth. Loss of function of TRIM28 leads to dysregulation of cell cycle, cellular response to stress, cancer cell metabolism, and inhibition of oxidative phosphorylation. All these mechanisms directly regulate maintenance of CSC population. Our original results revealed the role of the TRIM28 in regulating the CSC population in breast cancer. These findings may pave the way to novel and more effective therapies targeting cancer stem cells in breast tumors.