BKS0349 通过抑制 KIF20A 减少异种移植小鼠模型中的子宫内膜异位症病灶。
Inhibition of KIF20A by BKS0349 reduces endometriotic lesions in a xenograft mouse model.
机构信息
Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), Research Department Valencia, Spain.
INCLIVA Biomedical Research Institute, Research Department Valencia, Spain.
出版信息
Mol Hum Reprod. 2019 Sep 1;25(9):562-571. doi: 10.1093/molehr/gaz044.
Several studies have suggested a possible etiological association between ovarian endometriosis and ovarian cancer. Evidence has shown that KIF20A overexpression might confer a malignant phenotype to ovarian tumors by promoting proliferation and inhibiting apoptosis. However, no data about the role of KIF20A in endometriosis have been described. In this study, the human endometrium (n = 4) was transfected by mCherry adenovirus and intraperitoneally implanted in mice. Subsequently, mice were divided in three groups (n = 8/group) that were treated with Vehicle, BKS0349 (KIF20A-antagonist) or cabergoline (dopamine receptor agonist) for 21 days. mCherry-labeled endometriotic lesions were monitored over time using the IVIS Imaging System. Mice were sacrificed 72 h after the last administration; proliferation was evaluated by immunohistochemistry and apoptosis by TUNEL. CCND1 gene expression (G1 phase-related gene) was measured by qRT-PCR. A significant reduction in mCherry-fluorescent signal was observed in the BKS0349 group after treatment ended (D24) compared with D0 (P-value = 0.0313). Moreover, the mCherry signal on D24 showed a significant decrease in the BKS0349 group compared with controls (P-value = 0.0303), along with significant size reduction of endometriotic lesions observed in the BKS0349 group compared with control on D24 (P-value = 0.0006). Functional studies showed a significant reduction in proliferating cells in the BKS0349-treated group compared with controls (P-value = 0.0082). In addition, CCND1 expression was decreased in the BKS0349 group compared with control (P-value = 0.049) at D24 and a significant increase in apoptotic cells among endometriotic lesions in BKS0349-treated mice was observed compared with control (P-value = 0.0317). Based on these findings, we concluded that BKS0349 induces apoptosis and inhibits cell proliferation, reducing endometriotic lesion size and suggesting KIF20A inhibition by BKS0349 as a novel therapeutic treatment for endometriosis.
几项研究表明，卵巢子宫内膜异位症和卵巢癌之间可能存在病因关联。有证据表明，KIF20A 过表达可能通过促进增殖和抑制凋亡赋予卵巢肿瘤恶性表型。然而，目前尚无关于 KIF20A 在子宫内膜异位症中作用的描述。在这项研究中，用 mCherry 腺病毒转染人子宫内膜（n = 4），并将其腹膜内植入小鼠体内。随后，将小鼠分为三组（每组 n = 8），分别用载体、BKS0349（KIF20A 拮抗剂）或卡麦角林（多巴胺受体激动剂）处理 21 天。使用 IVIS 成像系统随时间监测 mCherry 标记的子宫内膜异位病变。最后一次给药后 72 小时处死小鼠；通过免疫组织化学评估增殖，通过 TUNEL 评估凋亡。通过 qRT-PCR 测量 CCND1 基因表达（G1 期相关基因）。与处理前（D0）相比，BKS0349 组在治疗结束后（D24）的 mCherry 荧光信号明显减少（P 值= 0.0313）。此外，与对照组相比，BKS0349 组在 D24 的 mCherry 信号明显减少（P 值= 0.0303），并且在 D24 时 BKS0349 组的子宫内膜异位病变大小明显减小与对照组相比（P 值= 0.0006）。功能研究表明，与对照组相比，BKS0349 治疗组增殖细胞明显减少（P 值= 0.0082）。此外，与对照组相比，BKS0349 组在 D24 时 CCND1 表达减少（P 值= 0.049），并且在 BKS0349 治疗的小鼠中观察到子宫内膜异位病变中的凋亡细胞明显增加与对照组相比（P 值= 0.0317）。基于这些发现，我们得出结论，BKS0349 诱导凋亡并抑制细胞增殖，减小子宫内膜异位病变的大小，并表明 BKS0349 通过抑制 KIF20A 作为子宫内膜异位症的一种新的治疗方法。
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