Wang Ruihuan, Shen Jie, Wang Qing, Zhang Minjuan
The Second Hematology Department, Cangzhou Central Hospital, 061001, China.
The Second Hematology Department, Cangzhou Central Hospital, 061001, China.
Biomed Pharmacother. 2018 Dec;108:43-49. doi: 10.1016/j.biopha.2018.08.151. Epub 2018 Sep 11.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, which is an aggressive malignancy with high variance of clinical features and response to the treatment. The proteasome inhibitor bortezomib (BTZ) has been demonstrated to suppress the progression of DLBCL, however, the underlying molecular mechanisms by which BTZ regulates the growth of DLBCL cells remain largely unknown. Increasing evidence has suggested that microRNAs (miRNAs) are novel targets of anti-cancer drugs to modulate the progression of cancers. Here, we showed BTZ treatment significantly inhibited the proliferation of DLBCL CRL-2630 cells. Mechanistically, exposure of BTZ up-regulated the expression of miR-198 in DLBCL cells. Depletion of miR-198 significantly reversed the inhibitory effect of BTZ on the proliferation of CRL-2630 cells. To further characterize the involvement of miR-198 in BTZ-induced growth defects of CRL-2630 cells, the downstream targets of miR-198 were predicted with the bioinformatics tools. The results showed that miR-198 bound the 3'-untranslated region (UTR) of the high mobility group AT-hook 1 (HMGA1) and suppressed the expression of HMGA1 in DLBCL cells. Consistently, BTZ treatment decreased the level of HMAG1 and inhibited the migration of DLBCL cells. Our results provided the possible mechanism by which BTZ suppressed the growth of DLBCL cells.
弥漫性大B细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤最常见的亚型，是一种侵袭性恶性肿瘤，临床特征和对治疗的反应差异很大。蛋白酶体抑制剂硼替佐米（BTZ）已被证明可抑制DLBCL的进展，然而，BTZ调节DLBCL细胞生长的潜在分子机制仍 largely 未知。越来越多的证据表明，微小RNA（miRNA）是抗癌药物调节癌症进展的新靶点。在这里，我们表明BTZ治疗显著抑制了DLBCL CRL-2630细胞的增殖。机制上，BTZ处理上调了DLBCL细胞中miR-198的表达。miR-198的缺失显著逆转了BTZ对CRL-2630细胞增殖的抑制作用。为了进一步表征miR-198在BTZ诱导的CRL-2630细胞生长缺陷中的作用，使用生物信息学工具预测了miR-198的下游靶点。结果表明，miR-198结合高迁移率族AT钩蛋白1（HMGA1）的3'非翻译区（UTR）并抑制DLBCL细胞中HMGA1的表达。一致地，BTZ处理降低了HMAG1的水平并抑制了DLBCL细胞的迁移。我们的结果提供了BTZ抑制DLBCL细胞生长的可能机制。
