Oncogene：找到治療致命性兒童骨癌的新希望

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　　導讀：猶他州大學Huntsman癌癥研究所的研究人員在研究垃圾DNA(junk DNA)過程中，意外發現尤文氏肉瘤(Ewing''s sarcoma)患者體內一種名為GSTM4的蛋白質高水平表達時，會抑制化療的效果。這項研究或許有助于研發針對抑制某些患者體內GSTM4表達水平的藥物。該研究發表在Oncogene雜志網絡版上。

　　尤文氏肉瘤是一種多發于兒童和青少年的常見骨癌。在這項研究中，研究人員的關注點為尤文氏肉瘤中一種名為EWS-FLI的異常蛋白。他們發現，EWS-FLI蛋白能引起GSTM4基因總量的增加，而GSTM4基因在腫瘤中表達GSTM4蛋白，該蛋白的過量表達使得對該疾病的化療收效甚微。

　　該結果是科學家研究微衛星序列時發現的。微衛星序列是基因組中的非編碼序列，因此也被稱為垃圾DNA。通過檢測EWS-FLI蛋白與微衛星序列之間的相互作用，研究人員發現了GSTM4的功能。

　　推薦原始出處：

　　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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　　腫瘤科藥師溫馨提醒：骨癌的早期癥狀還可能會出現患部皮膚潰爛等表現，患部的關節和肢體運動可能受到限制。同時，患者會感覺到患部疼痛，關節與肢體有局部腫塊及腫脹。這些都是骨癌的主要癥狀表現。

TAG：骨癌 兒童骨癌