Functional analysis of 11q13.5 amplicon identifies Rsf-1 (HBXAP) as a gene involved in paclitaxel resistance in ovarian cancer.
Functional analysis of 11q13.5 amplicon identifies Rsf-1 (HBXAP) as a gene involved in paclitaxel resistance in ovarian cancer.
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DOI：
10.1158/0008-5472.can-08-3602
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Shih, Ie-Ming
中科院分区：
文献类型：
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作者：
Choi, Jung Hye;Sheu, Jim Jinn-Chyuan;Guan, Bin;Jinawath, Natini;Markowski, Paul;Wang, Tian-Li;Shih, Ie-Ming
染色体11q13.5位点在几种类型的人类癌症中经常被扩增。我们之前已经证明，11q13.5的扩增与卵巢癌患者的总生存期显著缩短有关，但该基因扩增如何促进疾病侵袭性的分子机制尚不清楚。由于卵巢癌的死亡率主要与化疗药物的耐药性有关，我们筛选了该扩增子中排名前六的候选基因，以确定它们对耐药性的贡献。RSF-1(也称为HBXAP)被发现是唯一一个基因敲除使肿瘤细胞对紫杉醇敏感的基因。已知RSF-1与hSNF2H相互作用形成ISWI染色质重塑复合体。我们发现RSF-1在紫杉醇耐药的卵巢癌细胞株中表达上调，并且RSF-1在原发卵巢癌组织中的表达与体外紫杉醇耐药相关。RSF-1异位表达显著增强卵巢癌细胞对紫杉醇的耐药性。HSNF2H下调或hSNF2H与RSF-1相互作用中断可增强RSF-1上调的肿瘤细胞对紫杉醇的敏感性。RSF-1的表达改变了几个基因的表达，并激活了可能导致耐药性的某些信号通路。综上所述，我们的结果表明，RSF-1是11q13.5扩增子中导致紫杉醇耐药的主要基因，并且RSF-1/hSNF2H复合体的形成是诱导这种表型所必需的。
The chromosome 11q13.5 locus is frequently amplified in several types of human cancer. We have previously shown that 11q13.5 amplification was associated with significantly shorter overall survival in ovarian cancer patients but the molecular mechanisms of how amplification of this locus contributes to disease aggressiveness remain unclear. As ovarian cancer mortality is primarily related to resistance of chemotherapeutic agents, we screened the top six candidate genes within this amplicon for their contribution to drug resistance. Rsf-1 (also known as HBXAP) was found to be the only gene in which gene knockdown sensitized tumor cells to paclitaxel. Rsf-1 has been known to interact with hSNF2H to form an ISWI chromatin remodeling complex. We found that Rsf-1 was upregulated in paclitaxel resistant ovarian cancer cell lines and Rsf-1 immunoreactivity in primary ovarian carcinoma tissues correlated with in vitro paclitaxel resistance. Ectopic expression of Rsf-1 significantly enhanced paclitaxel resistance in ovarian cancer cells. Downregulation of hSNF2H or disruption of hSNF2H and Rsf-1 interaction enhanced paclitaxel sensitivity in tumor cells with Rsf-1 upregulation. Rsf-1 expression altered expression in several genes and activated certain signaling pathways that may contribute to drug resistance. In conclusion, our results suggest that Rsf-1 is the major gene within the 11q13.5 amplicon that contributes to paclitaxel resistance and the formation of the Rsf-1/hSNF2H complex is required for inducing this phenotype.