Zheng Peihao, Guo Honggang, Li Guangchao, Han Siqi, Luo Fei, Liu Yi
Department of Hematology, Navy General Hospital, Beijing 100048, China.
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
Biochem Biophys Res Commun. 2015 Mar 6;458(2):328-33. doi: 10.1016/j.bbrc.2015.01.110. Epub 2015 Feb 3.
Proteasomal subunit PSMB4, was recently identified as potential cancer driver genes in several tumors. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we investigated the expression and roles of PSMB4 in multiple myeloma (MM). We found a significant up-regulation of PSMB4 in MM plasma and cell lines. Ectopic overexpression of PSMB4 promoted cell growth and colony forming ability of MM cells, whereas inhibition of PSMB4 led to a decrease of such events. Furthermore, our results demonstrated the up-regulation of miR-21 and a positive correlation between the levels of miR-21 and PSMB4 in MM. Re-expression of miR-21 markedly rescued PSMB4 knockdown-mediated suppression of cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of miR-21, PSMB4 knockdown or NF-κB inhibition suppressed miR-21 expression in MM cells. Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-κB-miR-21 signaling, which may represent promising targets for novel specific therapies.
蛋白酶体亚基PSMB4最近被确定为几种肿瘤中潜在的癌症驱动基因。然而，PSMB4在致癌过程中的调控机制仍不清楚。在本研究中，我们调查了PSMB4在多发性骨髓瘤（MM）中的表达及作用。我们发现MM血浆和细胞系中PSMB4显著上调。PSMB4的异位过表达促进了MM细胞的生长和集落形成能力，而抑制PSMB4则导致这些事件减少。此外，我们的结果表明MM中miR-21上调，且miR-21水平与PSMB4之间呈正相关。miR-21的重新表达显著挽救了PSMB4敲低介导的细胞增殖和克隆形成抑制。此外，虽然PSMB4的强制表达显著增加了NF-κB活性和miR-21水平，但PSMB4敲低或NF-κB抑制可抑制MM细胞中miR-21的表达。综上所述，我们的结果表明PSMB4部分通过激活NF-κB-miR-21信号通路调节MM细胞生长，这可能代表了新型特异性治疗的有希望的靶点。
