Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment.
Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment.
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子宫平滑肌瘤是女性生殖系统最常见的良性肿瘤。肥胖个体有较高的子宫平滑肌瘤负担，但肥胖与子宫平滑肌瘤发展的相关机制尚不清楚。在本研究中，我们观察了脂肪细胞共培养和瘦素处理对人子宫肌瘤和平滑肌瘤细胞的影响。我们从子宫切除术或子宫肌瘤切除术患者中分离原发性平滑肌瘤和子宫内膜细胞。磷酸化ERK1/2/总ERK1/2、磷酸化STAT3/总STAT3、磷酸化AKT1/2/3/总AKT1/2/3/总AKT1/2/3的蛋白表达水平在与人脂肪细胞共培养并经瘦素处理的永生化和原发平滑肌瘤和子宫肌瘤细胞中采用免疫印迹法进行量化。采用酶联免疫吸附试验（ELISA）评估经瘦素处理的永生化人肌层和平滑肌瘤细胞中的促炎、纤维化和血管生成因子。STAT3、ERK和AKT抑制剂对脂肪细胞培养的平滑肌瘤细胞系的影响进行了评估。脂肪细胞共培养和瘦素处理增加了JAK2/STAT3、MAPK/ERK和PI3K/AKT信号的表达，而抑制剂抑制了这种作用。瘦素通过上调人平滑肌瘤细胞中的促炎因子（IFNγ、IL-8、IL-6、GM-CSF、MCP-1和TNF-α）、纤维化因子（TGF-β1、TGF-β2和TGF-β3）和血管生成因子（VEGF-A、HGF和Follistatin）诱导肿瘤友好微环境。此外，脂肪细胞共培养和瘦素处理通过激活MAPK/ERK、JAK2/STAT3和PI3k/AKT信号通路来促进平滑肌瘤细胞的生长。最后，STAT3、ERK和AKT抑制剂抑制了脂肪细胞共培养和瘦素处理的平滑肌瘤细胞的PCNA、TNF-α、TGF-β3和VEGF-A细胞内染色强度。这些发现表明，在肥胖女性中，脂肪细胞分泌激素或脂肪细胞可能通过激活瘦素受体信号通路促进平滑肌瘤的发展和生长。
Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1/2/total ERK1/2, phosphorylated STAT3/total STAT3, and phosphorylated AKT1/2/3/total AKT1/2/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2/STAT3, MAPK/ERK, and PI3K/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFNγ, IL-8, IL-6, GM-CSF, MCP-1, and TNF-α), fibrotic (TGF-β1, TGF-β2, and TGF-β3), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-α, TGF-β3, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways.