The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2
The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2
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DOI：
10.1002/jcp.22781
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发表时间：
2012-02-01
影响因子：
5.6
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Hamada, Shin;Satoh, Kennichi;Shimosegawa, Tooru
胰腺癌是危及生命的癌症之一，因为治愈手术的难度和对传统治疗策略的抵抗。最近的研究表明，癌症干细胞作为整个癌症组织中的少量细胞存在，有助于疾病的进展。癌症干细胞显示出对传统化疗的抵抗力，这源于多种转运蛋白基因的高表达。我们之前的研究证明了同源框基因 MSX2 作为上皮-间质转化诱导剂的加重作用，并且在当前研究中 MSX2 与化疗耐药相关。对 MSX2 靶基因的综合分析已确定 ABCG2 是负责基因。由于先前的研究报道了ABCG2作为癌症干细胞的决定因素的关键作用，因此研究了MSX2对ABCG2表达的详细调节机制。结果，每个细胞系中的MSX2表达水平与ABCG2表达水平良好相关，并且通过过表达或基于siRNA的敲低改变MSX2表达水平相应地影响ABCG2表达。最后，我们确定了 MSX2 和 SP1 通过 ABCG2 启动子内的 SP1 结合元件在 ABCG2 转录调控中的功能合作。这些发现阐明了癌症干细胞相关基因的有趣调控机制，并将描绘出胰腺癌的新治疗靶点。 J.细胞。生理学。 (C) 2011 年 Wiley 期刊公司。
Pancreatic cancer is one of the life-threatening cancers due to the difficulty in the curative surgery and resistance against conventional therapeutic strategies. Recent studies indicated that cancer stem cells, which exist as a small number of cells within the entire cancer tissue, contribute to the disease progression. Cancer stem cells reveal resistance against conventional chemotherapy, which is derived from the high-expression of multiple transporter genes. Our previous study demonstrated the aggravating role of the homeobox gene MSX2 as an inducer of epithelial-mesenchymal transition, and MSX2 turned out to correlate with the chemoresistance in the current study. Comprehensive analysis of the MSX2-target gene has identified ABCG2 as the responsible gene. Since previous studies reported the pivotal role of ABCG2 as a determining factor of cancer stem cells, the detailed regulatory mechanism of ABCG2 expression by MSX2 was investigated. As a result, the MSX2 expression level in each cell line well correlated with the ABCG2 expression level, and alteration of the MSX2 expression level by over-expression or siRNA-based knockdown affected the ABCG2 expression accordingly. Finally, we identified the functional cooperation of MSX2 and SP1 in the transcriptional regulation of ABCG2 via the SP1 binding elements within the ABCG2 promoter. These findings clarified the intriguing regulatory mechanism of the cancer stem cell-related gene, and will delineate a novel therapeutic target in pancreatic cancer. J. Cell. Physiol. (C) 2011 Wiley Periodicals, Inc.