Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma
Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma
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DOI：
10.1038/onc.2013.177
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发表时间：
2014-04-24
期刊：
影响因子：
8
通讯作者：
Tagawa, H.
中科院分区：
文献类型：
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作者：
Teshima, K.;Nara, M.;Tagawa, H.
原癌基因BMI1及其产物BMI1在各种类型的肿瘤中过表达，特别是在侵袭性肿瘤和对常规化疗有抗性的肿瘤中。BMI1/ BMI1也至关重要地参与癌症启动细胞的维持，并在套细胞淋巴瘤（MCL）中反复上调，特别是侵袭性变异体。最近，侧群（SP）细胞在各种类型的肿瘤中显示出肿瘤启动特性。在这项研究中，我们发现复发性MCL病例明显表现出BMI1/ BMI1的上调。我们进一步证明克隆源性MCL SP具有高致瘤性和自我更新能力等肿瘤启动特性，并且BMI1在复发性MCL病例和MCL细胞系的SP中上调。在筛选BMI1的上游调节因子时，我们发现MCL SP细胞中的microRNA-16 （miR-16）的表达通过调节SPs中的BMI1而下调，导致淋巴瘤异种移植后肿瘤大小减小。此外，为了研究BMI1在MCL中的下游靶点，我们对MCL细胞系进行了交联/染色质免疫沉淀实验，发现BMI1直接调控促凋亡基因BCL2L11/Bim和PMAIP1/Noxa，从而增强MCL的抗凋亡潜能。最后，我们发现最近用于复发性MCL的蛋白酶体抑制剂硼替佐米可以有效诱导MCL细胞凋亡，同时降低MCL SP中Bmi1的表达，增加miR-16的表达。这些结果表明，MCL SP中Bmi1的上调和miR-16的下调通过减少MCL细胞凋亡在疾病的进展中起关键作用。我们的研究结果为MCL的发病机制提供了重要的新见解，并强烈建议靶向BMI1/ BMI1可能是治疗MCL的有效方法，特别是难治性和复发性MCL。
The proto-oncogene BMI1 and its product, Bmi1, is overexpressed in various types of tumors, particularly in aggressive tumors and tumors resistant to conventional chemotherapy. BMI1/Bmi1 is also crucially involved in cancer-initiating cell maintenance, and is recurrently upregulated in mantle cell lymphoma (MCL), especially aggressive variants. Recently, side population (SP) cells were shown to exhibit tumor-initiating characteristics in various types of tumors. In this study, we show that recurrent MCL cases significantly exhibit upregulation of BMI1/Bmi1. We further demonstrate that clonogenic MCL SP shows such tumor-initiating characteristics as high tumorigenicity and self-renewal capability, and that BMI1 was upregulated in the SP from recurrent MCL cases and MCL cell lines. On screening for upstream regulators of BMI1, we found that expression of microRNA-16 (miR-16) was downregulated in MCL SP cells by regulating Bmi1 in the SPs, leading to reductions in tumor size following lymphoma xenografts. Moreover, to investigate downstream targets of BMI1 in MCL, we performed cross-linking/chromatin immunoprecipitation assay against MCL cell lines and demonstrated that Bmi1 directly regulated pro-apoptotic genes such as BCL2L11/Bim and PMAIP1/Noxa, leading to enhance anti-apoptotic potential of MCL. Finally, we found that a proteasome inhibitor bortezomib, which has been recently used for relapsed MCL, effectively induced apoptosis among MCL cells while reducing expression of Bmi1 and increasing miR-16 in MCL SP. These results suggest that upregulation of BMI1 and downregulation of miR-16 in MCL SP has a key role in the disease's progression by reducing MCL cell apoptosis. Our results provide important new insight into the pathogenesis of MCL and strongly suggest that targeting BMI1/Bmi1 might be an effective approach to treating MCL, particularly refractory and recurrent cases.