MMP-2和MMP-9在CCR9介导的急性T淋巴细胞白血病转移中的分子机制研究

Recently, many studies have shown that chemokines and their receptors play an important role in the process of tumor metastasis. Our previous studies have confirmed that high expression of CCR9 on the lymphocytes of patients with T–lineage acute lymphocytic leukemia (T-ALL) is closely related to tumor metastasis. Other studies have reported that metastasis of acute lymphocytic leukemia cells is related with the high expression of Matrix metalloproteinase 2 (MMP-2) and Matrix metalloproteinase 9 (MMP-9), and that CCL25/CCR9 can promote the expression of MMP-2, 9 and enhance the metastasis of tumor cells in prostate cancer. However there has been no evidence to suggest that CCR9, MMP-2 and MMP-9 are involved in the metastasis of T-ALL. We therefore intend to investigate whether MMP-2 and MMP-9 play key roles in the metastasis of T-ALL in MOLT4 cells and T-ALL clinical samples by employing RNAi, RT-PCR, Western Blot techniques. Our research will shed light on the molecular mechanisms of metastasis of T-ALL thereby providing new clues in the treatment of T-ALL.

近年来的研究表明趋化性细胞因子及其受体在肿瘤的转移过程中发挥着重要作用。我们的前期研究发现，CCR9在急性T淋巴细胞白血病(T-ALL)患者的白血病细胞上异常高表达，并与T-ALL的转移密切相关；另有报道，急性淋巴细胞性白血病细胞的转移与基质金属蛋白激酶MMP-2、MMP-9异常高表达有关；并且前列腺癌中CCL25/CCR9可促进MMP-2、9的表达，增强肿瘤细胞的转移能力；而有关CCR9与MMP-2、MMP-9参与T-ALL浸润转移的研究国内外尚未见报道。本研究拟以天然高表达CCR9的T-ALL细胞系MOLT4及临床样本为研究对象，运用RNAi、RT-PCR、Western Blot等技术，试图证实在CCL25/CCR9介导的T-ALL转移过程中，MMP-2和MMP-9 起着关键作用。以期进一步阐明T-ALL转移的分子机制，为治疗T-ALL提供新的线索。

基质金属蛋白酶（MMPs）参与多种生理和病理过程。我们分析了来自Gene Expression Omnibus数据库的11个数据集，发现MMP7和MMP15在多种癌中高表达。 GSE13204显示MMP7和MMP15在急性髓性白血病（AML）患者中过表达。癌症基因组图谱数据集显示，AML患者骨髓（BM）中MMP7或MMP15的高表达预示总体存活率较低。卡方检验结果表明，MMP7和MMP15的高表达水平与AML患者的危险分级和骨髓中白血病细胞百分率相关。为了验证这些结果，我们进行了RT-qPCR，发现MMP7和MMP15在3种AML细胞系中高表达。我们进一步的研究表明，与健康个体相比，收集的AML样本中MMP7和MMP15在BM和外周血中均呈高表达。另外，AML患者的BM样品的lncRNA微阵列显示多个lncRNA与MMP7和MMP15相关，表明lncRNA可能通过调节MMP参与AML的发病机制。我们的研究揭示了MMP7和MMP15在AML预后中的潜在作用。