长链非编码RNA-MEG3通过调控C-MYC/MUM1环路参与多发性骨髓瘤硼替佐米化疗敏感性调节的机制研究

Bortezomib influences the long-term survival of MM patients, while C-MYC/MUM1 positive feedback loop plays crucial role in regulating MM bortezomib chemosensitivity. Preliminary results showed: ①Patients with highly expressed MEG3 in MM bone marrow biopsy samples were sensitive to the treatment of bortezomib. And MEG3 also participanted in the sensibilization of MM cell to bortezomib. ②MEG3 was negatively associated with C-MYC and MUM1 in MM bone marrow biopsy samples and MEG3 could downregulating the mRNA stability of C-MYC and MUM1 in MM cell. ③Bioinformatics analysis and experiments showed that MEG3 could competitively bind to RNA binding protein PTBP1 and FUS. Besides, bioinformatics analysis showed that PTBP1 and FUS could respectively bind to C-MYC and MUM1. ④Knocking out PTBP1 or FUS could both downregulate the expression of C-MYC and MUM1 and enhance bortezomib chemosensitivity in MM cell. Accordingly, we proposed that MEG3 could competitively bind to FUS and PTBP1 and thus inhibiting the C-MYC/MUM1 positive feedback loop, which finally sensitize MM to bortezomib treatment. This program aims to explore the mechanisms through which MEG3 may sensitize MM to bortezomib at molecular, cellular, animal and population level and offer new ideas for the research of bortezomib resistance.

硼替佐米化疗抵抗制约了MM患者的长期生存，C-MYC/MUM1环路在MM硼替佐米化疗敏感性的调节中发挥重要作用。前期研究发现：①硼替佐米化疗患者骨髓组织中MEG3高表达则预后更佳，过表达MEG3能参与MM细胞硼替佐米化疗增敏；②MM骨髓中MEG3表达与C-MYC及MUM1表达呈负相关，过表达MEG3能降低MM细胞中C-MYC及MUM1的mRNA稳定性；③生物信息及RNA-pulldown实验证实MEG3可与RNA结合蛋白PTBP1及FUS结合；预测发现PTBP1及FUS能分别与C-MYC及MUM1结合；④敲低PTBP1或FUS能下调C-MYC及MUM1的表达，且参与MM细胞硼替佐米的化疗增敏。据此提出假说：MEG3可作为PTBP1及FUS的蛋白诱饵调控C-MYC/MUM1环路，进而参与MM硼替佐米化疗敏感性的调节。本项目将从分子、细胞、动物、人群层面探索，为MM硼替佐米耐药研究提供新思路。