miR-377-dependent BCL-xL regulation drives chemotherapeutic resistance in B-cell lymphoid malignancies.
miR-377-dependent BCL-xL regulation drives chemotherapeutic resistance in B-cell lymphoid malignancies.
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DOI：
10.1186/s12943-015-0460-8
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发表时间：
2015-11-04
期刊：
影响因子：
37.3
通讯作者：
Almasan A
中科院分区：
文献类型：
--
作者：
Al-Harbi S;Choudhary GS;Ebron JS;Hill BT;Vivekanathan N;Ting AH;Radivoyevitch T;Smith MR;Shukla GC;Almasan A
BCL-xL是一种抗凋亡BCL-2家族蛋白，其抑制凋亡并在许多癌症中过表达。我们已经报道了对BCL-2抑制剂ABT-199（维奈托克）的获得性耐药性与BCL-xL表达增加相关。然而，BCL-xL如何介导造血系统恶性肿瘤的化疗耐药性尚不清楚。这一发现可能有助于设计新的治疗干预策略，以克服BCL-xL介导的获得性耐药性。我们现在发现，在ABT-199耐药细胞中，BCL-xL表达的增加与miR-377的表达呈负相关。这一发现还扩展到一组B细胞淋巴系和原发性慢性淋巴细胞白血病（CLL）细胞。miR-377通过识别BCL-xL 3 '-UTR中的两个结合位点抑制BCL-xL表达。这两个miR-377共有结合位点的突变完全消除了其调节作用。miR-377模拟物的表达下调BCL-xL蛋白表达并显著增加凋亡性细胞死亡。miR-377抑制剂的表达恢复了BCL-xL蛋白的表达，并限制了由低甲基化剂5-氮杂胞苷引起的细胞死亡。因此，miR-377依赖性BCL-xL调节驱动对ABT-199的获得性治疗抗性。我们进一步表明，接受各种化疗方案的CLL患者也具有显著较高的BCL-xL和较低的miR-377表达，表明暴露于化疗可能引发miR-377的转录沉默，从而导致高水平的BCL-xL。重要的是，具有高BCL-xL/低miR-377表达的CLL患者具有晚期肿瘤阶段。此外，在76例CLL患者中，高BCL-xL表达与短无治疗生存期相关。miR-377位于DLK 1-DIO 3区域的14 q32，其编码人类中最大的肿瘤抑制miRNA簇。对另外5个14 q32 miRNAs的检测显示，大多数在大多数CLL患者以及ABT-199耐药细胞系中显著下调。值得注意的是，与未经治疗的患者相比，这些miRNA中的四种在化疗治疗的CLL患者中的表达显著降低。这些发现表明多种miRNA的表达减少，这可能反映了该miRNA簇在治疗抗性淋巴样细胞中的整体沉默。这些发现揭示了一种新的机制，通过这种机制，miR-377的下调增加了BCL-xL的表达，促进了B细胞淋巴恶性肿瘤的化疗耐药性。本文的在线版本（doi：10.1186/s12943-015-0460-8）包含补充材料，可供授权用户使用。
BCL-xL is an anti-apoptotic BCL-2 family protein that inhibits apoptosis and is overexpressed in many cancers. We have reported that acquired resistance to the BCL-2 inhibitor ABT-199 (venetoclax) is associated with increased BCL-xL expression. Yet, how BCL-xL mediates chemoresistance in hematopoietic malignancies is not clear. This finding may help in design of new strategies for therapeutic intervention to overcome acquired chemoresistance mediated by BCL-xL. We now show that the increased BCL-xL expression was inversely correlated with that of miR-377 in ABT-199-resistant cells. This finding was also extended to a panel of B-cell lymphoid lines and primary chronic lymphocytic leukemia (CLL) cells. miR-377 suppressed BCL-xL expression by recognizing two binding sites in the BCL-xL 3’-UTR. Mutation of these two miR-377 consensus-binding sites completely abolished its regulatory effect. Expression of a miR-377 mimic downregulated BCL-xL protein expression and significantly increased apoptotic cell death. Expression of a miR-377 inhibitor restored BCL-xL protein expression and limited cell death caused by the hypomethylating agent 5-azacytidine. Thus, miR-377-dependent BCL-xL regulation drives acquired therapeutic resistance to ABT-199. We further show that CLL patients who received a diverse array of chemotherapy regimens also had significantly higher BCL-xL and lower miR377 expression, indicating that exposure to chemotherapy might trigger transcriptional silencing of miR-377, which results in high levels of BCL-xL. Importantly, CLL patients with high BCL-xL/low miR-377 expression had an advanced tumor stage. Moreover, the high BCL-xL expression correlated with short treatment-free survival in 76 CLL patients. miR-377 is located at 14q32 in the DLK1-DIO3 region, which encodes the largest tumor suppressor miRNA cluster in humans. Examination of five additional 14q32 miRNAs revealed that the majority were significantly down-regulated in most CLL patients as well as in ABT-199-resistant cell lines. Remarkably, four of these miRNAs had significantly decreased expression in chemotherapy-treated CLL patients as compared to those untreated. These findings indicate a reduced expression of multiple miRNAs that may reflect a global silencing of this miRNA cluster in therapy-resistant lymphoid cells. These findings reveal a novel mechanism by which down-regulation of miR-377 increases BCL-xL expression, promoting chemotherapy resistance in B-cell lymphoid malignancies. The online version of this article (doi:10.1186/s12943-015-0460-8) contains supplementary material, which is available to authorized users.