Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma
Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma
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DOI：
10.1158/1535-7163.mct-07-2118
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发表时间：
2008-06-01
影响因子：
5.7
通讯作者：
Joshi, Shantaram S.
中科院分区：
文献类型：
--
作者：
Hegde, Ganapati V.;Munger, Corey M.;Joshi, Shantaram S.
套细胞淋巴瘤（MCL）是B细胞淋巴瘤中临床结局最差的一种，中位生存期仅为3 - 4年。因此，需要更好地理解调节MCL增殖/存活的潜在机制以开发有效的治疗。由于音刺猬（Shh）-GLI信号已被证明是重要的增殖和生存的几种癌症，没有这样的信息是可用于MCL，这项研究进行。我们的研究结果表明，与Shh-GLI信号传导相关的分子，如PTCH和SMO受体，以及GLI 1和GLI 2靶转录因子在人MCL细胞系和患者的原代MCL细胞中表达。在外源性Shh/环巴胺存在下，该信号的扰动显著（P < 0.001）影响JVM 2 MCL细胞的增殖。反义寡核苷酸下调GLI转录因子的表达不仅显著（P < 0.001）降低MCL细胞的增殖，而且显著（P < 0.05）增加其对化疗药物阿霉素的敏感性。GLI的下调也降低了cyclin D1和BCL 2的转录水平，这表明这些关键分子可能在MCL中受到GLI的调节。因此，我们的研究结果表明Shh-GLI信号转导在MCL增殖中起重要作用，并且GLI的分子靶向是改善MCL治疗的潜在治疗方法。
Mantle cell lymphoma (MCL) has one of the worst clinical outcomes among the B-cell lymphomas, with a median survival of only 3 to 4 years. Therefore, a better understanding of the underlying mechanisms that regulate MCL proliferation/survival is needed to develop an effective therapy. Because sonic hedgehog (Shh)-GLI signaling has been shown to be important in the proliferation and survival of several cancers, and no such information is available for MCL, this study was undertaken. Our results show that the molecules associated with Shh-GLI signaling, such as PTCH and SMO receptors, and GLI1 and GLI2 target transcription factors were expressed in the human MCL cell lines and primary MCL cells from patients. Perturbation of this signaling in the presence of exogenous Shh/cyclopamine significantly (P < 0.001) influenced the proliferation of JVM2 MCL cells. Furthermore, down-regulation of GLI transcription factors using antisense oligonucleotides not only resulted in significantly (P < 0.001) decreased proliferation of the MCL cells but also significantly (P < 0.05) increased their susceptibility to chemotherapeutic drug, doxorubicin. Also, down-regulation of GLI decreased cyclin D1 and BCL2 transcript levels, which suggests that these key molecules might be regulated by GLI in MCL. Thus, our results indicate a significant role for Shh-GLI signaling in the proliferation of MCL, and molecular targeting of GLI is a potential therapeutic approach to improve the treatment for MCL.