Visfatin stimulates endometrial cancer cell proliferation via activation of PI3K/Akt and MAPK/ERK1/2 signalling pathways
Visfatin stimulates endometrial cancer cell proliferation via activation of PI3K/Akt and MAPK/ERK1/2 signalling pathways
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Visfatin 通过激活 PI3K/Akt 和 MAPK/ERK1/2 信号通路刺激子宫内膜癌细胞增殖
DOI：
10.1016/j.ygyno.2016.07.109
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发表时间：
2016-10-01
影响因子：
4.7
通讯作者：
Xue, Fengxia
中科院分区：
文献类型：
--
作者：
Wang, Yingmei;Gao, Chao;Xue, Fengxia
Objective.子宫内膜癌是女性生殖系统最常见的恶性肿瘤之一，但其病因和发病机制尚不清楚，尽管脂肪因子如内脂素可能参与其中。我们的研究为内脂素在子宫内膜癌中的致瘤作用机制提供了新的见解。我们使用高分化石川细胞和低分化KLE细胞研究内脂素对子宫内膜癌细胞增殖、细胞周期和凋亡的影响。我们还评估了内脂素对体内肿瘤生长的影响。内脂素可促进石川和KLE细胞增殖，促进细胞G1/S期进程，抑制细胞凋亡。内脂素促进BALB/c-nu小鼠子宫内膜癌肿瘤生长。使用免疫组织化学染色分析来自子宫内膜癌小鼠模型的移植肿瘤组织，其显示Ki-67与过度丰富的内脂素的强得多的阳性信号。Westernblot分析显示，内脂素作用后，胰岛素受体（IR）、胰岛素受体底物（IRS）1/2以及磷脂酰肌醇3-激酶（PI 3 K）/AKT和丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）1/2信号通路的关键组分在子宫内膜癌细胞中均呈高表达。经处理的细胞显示C-MYC和细胞周期蛋白D1增加，caspase-3表达减少。PI 3 K抑制剂LY 294002和MEK抑制剂U 0126可阻断内脂素对细胞增殖和凋亡的影响。内脂素通过激活IR、PI 3 K/Akt和MAPK/ERK信号通路促进子宫内膜癌的恶性进展。内脂素可作为子宫内膜癌治疗的靶点。(C)2016 Elsevier Inc. All rights reserved.
Objective. Endometrial carcinoma is one of the most common malignancies of the female reproductive system, but the aetiology and pathogenesis are not well understood, although adipokines such as visfatin may be involved. Our study provides insight into the mechanism underlying the tumorigenic effects of visfatin in endometrial carcinoma.Methods. We investigated the effect of visfatin on endometrial carcinoma cell proliferation, cell cycle, and apoptosis using well-differentiated Ishikawa cells and poorly differentiated KLE cells. We also assessed the effect of visfatin on tumour growth in vivo.Results. Visfatin stimulated the proliferation of both Ishikawa and KLE cells, and visfatin treatment promoted G1/S phase progression and inhibited endometrial carcinoma cell apoptosis. Visfatin promoted endometrial carcinoma tumour growth in BALB/c-nu mice. Transplanted tumour tissues from an endometrial carcinoma mouse model were analysed using immunohistochemical staining, which revealed much stronger positive signals for Ki-67 with over-abundant visfatin. Western blot analysis revealed that insulin receptor (IR), insulin receptor substrate (IRS)1/2 and key components of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 signalling pathways were highly expressed in endometrial carcinoma cells exposed to visfatin. Treated cells showed increased C-MYC and cyclin D1 and reduced caspase-3 expression. The effects of visfatin on proliferation and apoptosis were abrogated by treatment with the PI3K inhibitor LY294002 and MEK inhibitor U0126.Conclusions. Visfatin promotes the malignant progression of endometrial carcinoma via activation of IR and PI3K/Akt and MAPK/ERK signalling. Visfatin may serve as a therapeutic target in the treatment of endometrial carcinoma. (C) 2016 Elsevier Inc. All rights reserved.