Department of Hematology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China.
Wannan Medical College, Wuhu 241001, China.
Life Sci. 2020 Sep 15;257:118088. doi: 10.1016/j.lfs.2020.118088. Epub 2020 Jul 12.
Bone marrow stromal cells (BMSCs) have been reported to interact with multiple myeloma (MM) and exert a vital function of the survival of MM cells. Heme oxygenase-1 (HO-1), a cytoprotective enzyme, has the potential to become a hematological malignancies targeted gene. This study aimed to investigate the role of HO-1 in MM resistance of BMSCs and its possible mechanisms.
In this study, the expression of related proteins was detected by RT-qPCR and Western blot. HO-1 expression was regulated by lentivirus transfection. Cell viability and apoptosis were detected by Flow cytometry and CCK-8. Cytokine secretion was assayed by ELISA. The survival and carcinogenic abilities was detected by clone formation assay.
HO-1 expression in the BMSCs of stage III MM patients was substantially increased, compared with that of healthy donors and stage I/II patients. The results of co-culture of BMSCs and MM cells indicated that, the upregulated HO-1 inhibited the apoptosis of co-cultured MM cells, while downregulated HO-1 promoted the chemosensitivity of co-cultured MM cells, moreover, the upregulated HO-1 in BMSCs increased the colony-formation ability of MM cells. This protective capability may be regulated by CXCL12/CXCR4 signaling. High HO-1 expression in BMSCs can promote the phosphorylation of the JAK2/STAT3 pathway, thereby increasing secretion of SDF-1 in BMSCs and activating CXCL12/CXCR4 signaling. In addition, direct contact between BMSCs and MM cells may cause drug resistance.
These results indicated that the regulation of HO-1 in BMSCs may be a new effective method of MM therapy.
骨髓基质细胞（BMSCs）已被报道与多发性骨髓瘤（MM）相互作用，并发挥 MM 细胞存活的重要功能。血红素加氧酶-1（HO-1）是一种细胞保护酶，具有成为血液恶性肿瘤靶向基因的潜力。本研究旨在探讨 HO-1 在 BMSCs 中对 MM 耐药的作用及其可能的机制。
本研究通过 RT-qPCR 和 Western blot 检测相关蛋白的表达。通过慢病毒转染调节 HO-1 的表达。通过流式细胞术和 CCK-8 检测细胞活力和凋亡。通过 ELISA 检测细胞因子分泌。通过集落形成实验检测细胞的存活和致癌能力。
与健康供体和 I/II 期患者相比，III 期 MM 患者的 BMSCs 中 HO-1 表达显著增加。BMSCs 和 MM 细胞共培养的结果表明，上调的 HO-1 抑制共培养 MM 细胞的凋亡，而下调的 HO-1 促进共培养 MM 细胞的化疗敏感性，此外，BMSCs 中上调的 HO-1 增加了 MM 细胞的集落形成能力。这种保护能力可能受 CXCL12/CXCR4 信号的调节。BMSCs 中高 HO-1 表达可促进 JAK2/STAT3 通路的磷酸化，从而增加 BMSCs 中 SDF-1 的分泌并激活 CXCL12/CXCR4 信号。此外，BMSCs 与 MM 细胞的直接接触可能导致耐药性。
这些结果表明，BMSCs 中 HO-1 的调节可能是 MM 治疗的一种新的有效方法。
