Wnt-β-catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer.
Wnt-β-catenin signaling regulates ABCC3 (MRP3) transporter expression in colorectal cancer.
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DOI：
10.1111/cas.13097
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发表时间：
2016-12
期刊：
影响因子：
5.7
通讯作者：
Nakayama K
中科院分区：
文献类型：
--
作者：
Kobayashi M;Funayama R;Ohnuma S;Unno M;Nakayama K
我们测定了48个三磷酸腺苷结合盒(ABC)转运体在匹配的结肠癌和正常结肠组织中的基因表达谱，以深入了解转运体与结肠癌发生相关的潜在机制。ABCB1、ABCC1、ABCC2、ABCC3和ABCG2的表达改变与结肠癌的发生有关。在这些转运蛋白中，ABCC3在结肠癌细胞系中的表达受Wnt信号通路的抑制。抑制转录因子7-样2(TCF7L2)或β-连环蛋白从而增加ABCC3的表达，而用糖原合成酶激酶-3β(GSK-3β)的抑制剂激活Wnt信号则降低其表达。ChIP和荧光素酶报告分析也表明TCF7L2与ABCC3基因结合并调节其表达。最后，ABCC3在结肠癌细胞中的过表达使其对抗癌药物诱导的细胞毒性具有抵抗力。因此，我们的数据表明，Wnt信号在结肠癌发生过程中抑制了ABCC3的表达，随后在药物治疗期间ABCC3的表达上调可能与获得性耐药有关。
We determined the gene expression profiles for 48 ATP binding cassette (ABC) transporters in matched colon cancer and normal colon tissues in order to provide insight into the mechanisms underlying expression of transporters related to colon carcinogenesis. The expression of ABCB1,ABCC1,ABCC2,ABCC3, and ABCG2 was altered in association with colon carcinogenesis. Among these transporters, the expression of ABCC3 was repressed by Wnt signaling pathway in colon cancer cell lines. Knockdown of the pathway components transcription factor 7‐like 2 (TCF7L2) or β‐catenin thus increased ABCC3 expression, whereas activation of Wnt signaling with inhibitors of glycogen synthase kinase–3β (GSK‐3β) reduced it. ChIP and luciferase reporter assays also showed that TCF7L2 binds to the ABCC3 locus and regulates its expression. Finally, overexpression of ABCC3 in colon cancer cells conferred resistance to anticancer drug‐induced cytotoxicity. Our data thus suggest that Wnt signaling represses ABCC3 expression during colon carcinogenesis, and that subsequent upregulation of ABCC3 expression during drug treatment might contribute to acquired drug resistance.
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影响因子：
3.1
作者：
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通讯作者：
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作者：
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影响因子：
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通讯作者：
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作者：
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通讯作者：
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