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Cancer Dis:乳腺癌预后新标志物转录因子ZNF217

来源:生物谷 2012-06-29 20:18

转录因子ZNF217是染色体20q13的扩增候选基因,20%至30%的原位乳腺癌肿瘤患者都表达转录因子ZNF217,ZNF217与乳腺癌患者预后较差呈相关性。

近日刊登在Cancer Discovery上的一则新研究证实,ZNF217过度表达驱动肿瘤细胞的异常分化,激活下游信号级联反应,这信号级联反应促进肿瘤细胞自我更新能力的提高、肿瘤细胞的间充质标志物表达升高,细胞运动和转移能力也上调。

研究人员用硅片筛选发现,该转录因子在低浓度时可抑制高表达ZNF217癌症细胞的生长。在体内研究中,核苷类似物曲西明(Triciribine)抑制ZNF217诱发的肿瘤生长和化疗耐药,其机制就是通过抑制如Akt的磷酸化、丝裂原活化蛋白激酶(MAPK)的磷酸化等信号。

由于在许多癌症中ZNF217的高表达,研究数据表明ZNF217是一种乳腺癌患者预后差的生物标志物,在过度表达ZNF217的乳腺癌患者中,曲西明(Triciribine)的治疗可能是化治疗策略的一个新方法。(生物谷:Bioon.com)

The Transcription Factor ZNF217 Is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression.

Littlepage LE, Adler AS, Kouros-Mehr H, Huang G, Chou J, Krig SR, Griffith OL, Korkola JE, Qu K, Lawson DA, Xue Q, Sternlicht MD, Dijkgraaf GJ, Yaswen P, Rugo HS, Sweeney CA, Collins CC, Gray JW, Chang HY, Werb Z.

The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers.

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