Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui 230032, P.R. China.
Oncol Rep. 2019 Jan;41(1):415-426. doi: 10.3892/or.2018.6797. Epub 2018 Oct 16.
The Snail family transcriptional repressor 1 gene (Snail1) was screened in multiple myeloma cells (MMCs) from bortezomib-resistant MM patients and was found to be significantly associated with the development of drug-resistance mechanisms. In the present study, we first confirmed that the protein expression of Snail1 in bortezomib-resistant MMCs was significantly higher than that in MMCs without bortezomib resistance. The mechanistic studies confirmed that the enhancement of Snail1 expression in bortezomib-resistant MMCs directly upregulated transcription of the intracellular MDR1 gene to immediately develop multiple drug resistance mechanisms and inhibited P53 protein expression through the Snail1/hsa-miRNA-22-3p/P53 pathway to inhibit tumor cell apoptosis. By upregulating MDR1 and downregulating P53, Snail1 induced the drug resistance of MMCs to bortezomib, while Snail1 gene silencing effectively improved the drug sensitivity of MMCs to bortezomib chemotherapy. The present study further elucidated the drug resistance mechanisms of MMCs and provides evidence for increased clinical efficacy of bortezomib in MM patients.
蜗牛家族转录抑制因子 1 基因（Snail1）在硼替佐米耐药多发性骨髓瘤患者的骨髓瘤细胞（MMCs）中被筛选出来，并且与耐药机制的发展显著相关。在本研究中，我们首先证实了硼替佐米耐药 MMC 中 Snail1 的蛋白表达明显高于无硼替佐米耐药的 MMC。机制研究证实，硼替佐米耐药 MMC 中 Snail1 表达的增强直接上调了细胞内 MDR1 基因的转录，从而迅速产生多种耐药机制，并通过 Snail1/hsa-miRNA-22-3p/P53 通路抑制 P53 蛋白表达，抑制肿瘤细胞凋亡。Snail1 通过上调 MDR1 并下调 P53，诱导 MMC 对硼替佐米的耐药性，而沉默 Snail1 基因可有效提高 MMC 对硼替佐米化疗的敏感性。本研究进一步阐明了 MMC 的耐药机制，为增加硼替佐米在 MM 患者中的临床疗效提供了依据。
