文章：

表达刺猬相互作用蛋白的基质细胞调控髓系肿瘤的增殖

Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms

原文发布日期：2012-09-07

DOI: 10.1038/bcj.2012.36

类型: Original Article

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英文摘要：

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34+ cells, CD34+ blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34+ acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO+ leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO+ leukemic cell proliferation. The demethylating agent, 5-aza-2′-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.

摘要翻译： 

刺猬信号（Hh）通路的异常再激活已在包括癌症干细胞在内的多种人类癌症中被广泛报道。然而，在髓系肿瘤发生过程中，Hh信号系统在骨髓微环境中的参与机制尚不明确。本研究评估了原发性人类CD34+细胞、CD34+原始细胞及骨髓基质细胞中Hh相关基因的表达情况。印度刺猬蛋白（Ihh）及其信号转导蛋白平滑化蛋白（SMO）在CD34+急性髓系白血病（AML）和骨髓增生异常综合征（MDS）来源细胞中均有表达，而Ihh在骨髓基质细胞中的表达相对较低。值得注意的是，AML/MDS来源基质细胞中内源性Hh信号抑制因子——人刺猬相互作用蛋白（HHIP）的表达显著低于健康供体来源的基质细胞。此外，骨髓基质细胞中HHIP的表达水平与其对SMO+白血病细胞的支撑活性高度相关。基质细胞中HHIP基因的敲低可增强其支撑活性，而对照组细胞对SMO+白血病细胞增殖的支撑作用微弱。去甲基化药物5-氮-2′-脱氧胞苷通过HHIP基因的去甲基化恢复了HHIP表达，并降低了AML/MDS来源基质细胞对白血病细胞的支撑活性。这表明基质细胞HHIP的抑制可能与AML/MDS细胞的增殖相关。

原文链接：

Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms