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Oncogene:找到治疗致命性儿童骨癌的新希望

来源:生命经纬 2009-09-04 09:40

犹他州大学Huntsman癌症研究所的研究人员在研究“垃圾DNA(junk  DNA)”过程中,意外发现尤文氏肉瘤(Ewing's  sarcoma)患者体内一种名为GSTM4的蛋白质高水平表达时,会抑制化疗的效果。这项研究或许有助于研发针对抑制某些患者体内GSTM4表达水平的药物。该研究发表在Oncogene杂志网络版上。

尤文氏肉瘤是一种多发于儿童和青少年的常见骨癌。在这项研究中,研究人员的关注点为尤文氏肉瘤中一种名为EWS-FLI的异常蛋白。他们发现,EWS-FLI蛋白能引起GSTM4基因总量的增加,而GSTM4基因在肿瘤中表达GSTM4蛋白,该蛋白的过量表达使得对该疾病的化疗收效甚微。

该结果是科学家研究微卫星序列时发现的。微卫星序列是基因组中的非编码序列,因此也被称为“垃圾DNA”。通过检测EWS-FLI蛋白与微卫星序列之间的相互作用,研究人员发现了GSTM4的功能。(生物谷Bioon.com)

生物谷推荐原始出处:

Oncogene 31 August 2009;doi: 10.1038/onc.2009.262

GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance

W Luo1,2, K Gangwal1,2, S Sankar1,2, K M Boucher1, D Thomas3 and S L Lessnick1,2,4

1Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA
2The Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
3Department of Pathology, University of Michigan, Ann Arbor, MI, USA
4Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, UT, USA

Ewing's sarcoma is a malignant bone-associated tumor of children and young adults. Most cases of Ewing's sarcoma express the EWS/FLI fusion protein. EWS/FLI functions as an aberrant ETS-type transcription factor and serves as the master regulator of Ewing's sarcoma-transformed phenotype. We recently showed that EWS/FLI regulates one of its key targets, NR0B1, through a GGAA-microsatellite in its promoter. Whether other critical EWS/FLI targets are also regulated by GGAA-microsatellites was unknown. In this study, we combined transcriptional analysis, whole genome localization data, and RNA interference knockdown to identify glutathione S-transferase M4 (GSTM4) as a critical EWS/FLI target gene in Ewing's sarcoma. We found that EWS/FLI directly binds the GSTM4 promoter, and regulates GSTM4 expression through a GGAA-microsatellite in its promoter. Reduction of GSTM4 levels caused a loss of oncogenic transformation. Furthermore, reduction of GSTM4 resulted in an increased sensitivity of Ewing's sarcoma cells to chemotherapeutic agents, suggesting a role for this protein in drug resistance. Consistent with this hypothesis, patients with Ewing's sarcoma whose tumors had higher levels of GSTM4 expression had worse outcomes than those with lower expression levels. These data show that GSTM4 contributes to the cancerous behavior of Ewing's sarcoma and define a wider role for GGAA-microsatellites in EWS/FLI function than previously appreciated. These data also suggest a novel therapeutic resistance mechanism, in which the central oncogenic abnormality directly regulates a resistance gene.

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