ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma.
ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma.
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DOI：
10.1038/onc.2011.195
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发表时间：
2011-12-08
期刊：
影响因子：
8
通讯作者：
Vega, F.
中科院分区：
文献类型：
--
作者：
Singh, R. R.;Kunkalla, K.;Qu, C.;Schlette, E.;Neelapu, S. S.;Samaniego, F.;Vega, F.
弥漫性大B细胞淋巴瘤(DLBCL)的成功治疗常常受到常规化疗耐药的阻碍，导致疾病复发和高死亡率。肿瘤信号通路诱导的抗细胞凋亡和/或药物转运蛋白的高表达与肿瘤化疗耐药的发生密切相关。此前，我们的研究表明，ATP结合盒药物转运体ABCG2在DLBCL中的高表达与无病无失败的生存呈负相关。在这项研究中，我们通过直接上调ABCG2基因的转录，推测激活的hedgehog(HH)信号通路是DLBCL高表达ABCG2的关键因素。我们已经确定了ABCG2启动子中GLI转录因子的单一结合位点，并通过荧光素酶报告、定点突变和染色质免疫沉淀试验确定了其功能。此外，在DLBCL肿瘤标本中，有淋巴结转移的DLBCL肿瘤组织中ABCG2和GLI1的水平显著高于胸腔积液和/或腹水中的DLBCL肿瘤细胞。这表明间质微环境在维持高水平的ABCG2和GLI1中发挥了作用。因此，DLBCL细胞与HS-5基质细胞体外共培养可通过旁分泌激活HH信号而增加ABCG2的mRNA和蛋白水平。除ABCG2外，DLBCL细胞与HS-5细胞共培养后，抗凋亡蛋白BCL2、BCL-XL和BCL2A1表达增加，对阿霉素和甲氨蝶呤耐药。同样，用重组Shh N端肽激活DLBCL细胞中的HH信号导致BCL2和ABCG2表达增加，这与化疗耐受性增加有关。FTC对ABCG2药物外排活性的功能性抑制或环多巴胺-KAAD抑制HH信号通路可消除基质诱导的化疗耐受，提示靶向ABCG2和HH信号通路在克服DLBCL化疗耐药方面有一定的治疗价值。
Successful treatment of diffuse large B-cell lymphoma (DLBCL) is frequently hindered by development of resistance to conventional chemotherapy resulting in disease relapse and high mortality. High expression of anti-apoptotic and/or drug transporter proteins induced by oncogenic signaling pathways has been implicated in the development of chemoresistance in cancer. Previously, our studies showed high expression of ATP-binding cassette drug transporter ABCG2 in DLBCL correlated inversely with disease-free and failure-free survival. In this study, we have implicated activated hedgehog (Hh) signaling pathway as a key factor behind high ABCG2 expression in DLBCL through direct upregulation of ABCG2 gene transcription. We have identified a single binding site for GLI transcription factors in the ABCG2 promoter and established its functionality using luciferase reporter, site-directed mutagenesis and chromatin-immunoprecipitation assays. Furthermore, in DLBCL tumor samples, significantly high ABCG2 and GLI1 levels were found in DLBCL tumors with lymph node involvement in comparison to DLBCL tumor cells collected from pleural and/or peritoneal effusions. This suggests a role for the stromal microenvironment in maintaining high levels of ABCG2 and GLI1. Accordingly, in vitro co-culture of DLBCL cells with HS-5 stromal cells increased ABCG2 mRNA and protein levels by paracrine activation of Hh signaling. In addition to ABCG2, co-culture of DLBCL cells with HS-5 cells also resulted in increase expression of the antiapoptotic proteins BCL2, BCL-xL and BCL2A1 and in induced chemotolerance to doxorubicin and methotrexate, drugs routinely used for the treatment of DLBCL. Similarly, activation of Hh signaling in DLBCL cell lines with recombinant Shh N-terminal peptide resulted in increased expression of BCL2 and ABCG2 associated with increased chemotolerance. Finally, functional inhibition of ABCG2 drug efflux activity with fumitremorgin (FTC) or inhibition of Hh signaling with cyclopamine-KAAD abrogated the stroma-induced chemotolerance suggesting that targeting ABCG2 and Hh signaling may have therapeutic value in overcoming chemoresistance in DLBCL.
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影响因子：
82.9
作者：
Dierks, Christine;Grbic, Jovana;Warmuth, Markus
通讯作者：
Warmuth, Markus
影响因子：
5.7
作者：
Baumann, Philipp;Mandl-Weber, Sonja;Schmidmaier, Ralf
通讯作者：
Schmidmaier, Ralf
影响因子：
7.3
作者：
Diestra, JE;Scheffer, GL;Izquierdo, MA
通讯作者：
Izquierdo, MA
影响因子：
20.3
作者：
Abbott, BL;Colapietro, AM;Sorrentino, BP
通讯作者：
Sorrentino, BP
DOI：
10.1073/pnas.95.26.15665
发表时间：
1998-12-22
影响因子：
11.1
作者：
Doyle, LA;Yang, WD;Ross, DD
通讯作者：
Ross, DD