Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Blood. 2012 Aug 23;120(8):1678-86. doi: 10.1182/blood-2012-02-410647. Epub 2012 Jul 13.
miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155-based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti-miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti-miR-155 delivered systemically showed uptake in the BM CD19(+) cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155-knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti-miR-155-mediated inhibition of miR-155 in the treatment of WM.
miR-155 在 B 细胞淋巴增殖性疾病中作为致癌 miR 发挥作用，包括华氏巨球蛋白血症（WM）和慢性淋巴细胞白血病，因此是治疗干预的潜在靶点。然而，在体内肿瘤细胞中高效靶向 miR 仍然是开发基于 miR-155 的治疗剂治疗 B 细胞恶性肿瘤的重大挑战。在本研究中，我们表明，针对 miR-155 种子区的 8 个碱基锁核酸抗 miR-155 寡核苷酸在体外抑制 WM 和慢性淋巴细胞白血病细胞的增殖。此外，全身性给予的抗 miR-155 可被 WM 移植小鼠的 BM CD19(+)细胞摄取，导致这些细胞中几个 miR-155 靶 mRNA 的上调，并显著抑制体内肿瘤生长。我们还发现，与对照样本相比，WM 患者的基质细胞中 miR-155 水平升高。有趣的是，miR-155 敲除小鼠的基质细胞导致 WM 肿瘤生长显著抑制，表明 miR-155 也可能通过 BM 微环境细胞促进 WM 增殖。本研究的结果强调了抗 miR-155 介导的 miR-155 抑制在 WM 治疗中的治疗潜力。
