Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors
Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors
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DOI：
10.1038/sj.onc.1209809
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发表时间：
2007-01-25
期刊：
影响因子：
8
通讯作者：
Powell, C. A.
中科院分区：
文献类型：
--
作者：
Borczuk, A. C.;Cappellini, G. C. A.;Powell, C. A.
恶性间皮瘤是一种源自浆膜内层细胞的侵袭性肿瘤增殖。上皮型恶性间皮瘤的生物学和临床特征不同于双相型和肉瘤型肿瘤。我们研究的目的是检查这种区别的分子基础。微阵列分析证实上皮和双相组织学亚型的分子特征是不同的。差异表达的功能基因类别包括泛素-蛋白酶体途径，该途径在双相肿瘤中表达上调。细胞毒性实验表明，源自双相肿瘤的211H细胞对含有蛋白酶体抑制剂硼替佐米和奥沙利铂的连续组合方案具有协同敏感性。这种协同反应的机制是细胞凋亡，但在上皮肿瘤来源的细胞中未检测到。总之，我们的结果确定泛素-蛋白酶体途径是双相性腹膜间皮瘤预后不良的生物标志物，并表明蛋白酶体抑制剂可以提高该亚类患者细胞毒性化疗的有效性。
Malignant mesothelioma is an aggressive neoplastic proliferation derived from cells lining serosal membranes. The biological and clinical characteristics of epithelial type malignant mesothelioma are distinct from those of biphasic and sarcomatous type tumors. The goal of our study was to examine the molecular basis for this distinction. Microarray analysis confirmed that the molecular signatures of epithelial and biphasic histologic subtypes were distinct. Among the differentially expressed functional gene categories was the ubiquitin-proteasome pathway, which was upregulated in biphasic tumors. Cytotoxicity experiments indicated that 211H cells derived from biphasic tumors were synergistically sensitive to sequential combination regimens containing the proteasome inhibitor bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of epithelial tumor origin, was apoptosis. Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.