Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin
Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin
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DOI：
10.1038/sj.onc.1207861
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发表时间：
2004-08-26
期刊：
影响因子：
8
通讯作者：
Hampton, GM
中科院分区：
文献类型：
--
作者：
Wagner, KW;Sapinoso, LM;Hampton, GM
基因表达专家。对解剖结构不同的癌症及其相应的正常组织进行LING，以确定与癌症相关表达的基因。我们发现泛素结合酶UbcH10在许多不同类型的癌症中显著过表达，并且与乳腺癌、肺癌、卵巢癌、膀胱癌以及胶质母细胞瘤的肿瘤分化程度有关。我们还表明，UbcH10在胃食道癌和其他癌症中的过度表达可能是UbcH10基因20q13.1位点染色体扩增的直接结果，该区域在各种肿瘤中都被扩增。为了评估抑制UbcH10功能是否可能与癌症的治疗相关，我们使用小干扰RNA(SiRNAs)选择性地沉默UbcH10转录。UbcH10表达的降低可显著抑制肿瘤细胞和正常细胞的增殖，而不会导致细胞死亡。然而，当与DR5/TRAIL受体激动剂结合时，针对UbcH10转录本的siRNAs显著增强了对癌细胞的杀伤，但对增殖的原代人类上皮细胞或成纤维细胞却没有。综上所述，这些数据表明，UbcH10在肿瘤的发展中起着重要的作用，它的抑制与TRAIL受体激动剂的结合可能提供一个增强的治疗指数。
Gene expression pro. ling of anatomically diverse carcinomas and their corresponding normal tissues was used to identify genes with cancer-associated expression. We show here that the ubiquitin conjugase, UbcH10, is significantly overexpressed in many different types of cancers and is associated with the degree of tumor differentiation in carcinomas of the breast, lung, ovary and bladder, as well as in glioblastomas. We also show that UbcH10 overexpression in gastro-esophageal, and probably other carcinomas may be a direct consequence of chromosomal amplification at the UbcH10 locus, 20q13.1, a region known to be amplified in diverse tumors. To evaluate whether inhibition of UbcH10 function may be therapeutically relevant in cancer, we used small interfering RNAs (siRNAs) to silence UbcH10 transcription selectively. Diminution of UbcH10 expression significantly inhibited both tumor and normal cell proliferation without inducing cell death. However, when combined with agonists of the DR5/TRAIL receptor, siRNAs directed against the UbcH10 transcript dramatically enhanced killing of cancer cells, but not of proliferating primary human epithelial cells or fibroblasts. Together, these data demonstrate that UbcH10 plays an important role in tumor development and that its inhibition in combination with agonists of the TRAIL receptor may provide an enhanced therapeutic index.