JPT2 in subclinical hypothyroidism-related miscarriage as a transcription co-factor: involvement of LEPR/STAT3 activation.

IF 5.4 2区 医学 Q1 Medicine Journal of Endocrinological Investigation Pub Date : 2024-10-01 Epub Date: 2024-06-22 DOI:10.1007/s40618-024-02343-0
Y-Y Zhou, S-Y Zhao, F-J Huang, L-J Zhang, Y-L Liu, J Wang, X-J Ma
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Abstract

Background and purpose: Subclinical hypothyroidism (SCH) has been identified to be associated with implantation failure, in which the dysfunction of trophoblast cells is involved. In this study, the transcriptomics of aborted placenta from SCH rats were analyzed. Jupiter microtubule-associated homolog 2 (JPT2) was downregulated in the aborted placenta. This study aims to investigate its role in SCH-associated miscarriage.

Methods: Spontaneous abortion was observed in SCH rats generated by thyroidectomy combined with levothyroxine administration. The transcriptomics analysis was performed using aborted placenta. Afterward, the effects of JPT2 on trophoblast cells were explored using gain-and loss-of-function experiments.

Results: Transcriptomics analysis showed 1286 downregulated genes and 2300 upregulated genes in the aborted placenta, and JPT2 was significantly downregulated in the aborted placenta from SCH rats. Afterward, gain-and loss-of-function experiments exhibited that overexpression of JPT2 promoted the proliferation, migration, invasion, spheroid formation of HTR-8/SVneo trophoblast cells and their attachment to endometrial stromal cells, while these biological behaviors were suppressed by JPT2 knockdown. Furthermore, JPT2 accelerated the transcription of leptin receptor (LEPR), and activated signal transducer and activator of transcription 3 (STAT3) signal in a transcription factor AP-2γ-dependent manner. In addition, silencing of LEPR abolished the role of JPT2.

Conclusion: Our results revealed that JPT2, which was downregulated in the aborted placenta from SCH rats, promoted proliferation, migration, invasion, spheroid formation, and attachment of trophoblast cells via regulating LEPR/STAT3 axis as a transcription co-factor. It is indicated that low expression of JPT2 may contribute to the abortion in individuals with SCH.

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亚临床甲状腺功能减退症相关流产中作为转录辅助因子的 JPT2:参与 LEPR/STAT3 激活。
背景和目的:亚临床甲状腺功能减退症(SCH)已被确认与植入失败有关,滋养层细胞的功能障碍与植入失败有关。本研究分析了 SCH 大鼠流产胎盘的转录组学。在流产胎盘中,木星微管相关同源物 2(JPT2)出现下调。本研究旨在探讨其在SCH相关流产中的作用:方法:在甲状腺切除术联合左甲状腺素给药的 SCH 大鼠中观察自然流产。采用流产胎盘进行转录组学分析。随后,利用功能增益和功能缺失实验探讨了 JPT2 对滋养层细胞的影响:结果:转录组学分析显示,流产胎盘中有1286个基因下调,2300个基因上调,JPT2在SCH大鼠流产胎盘中显著下调。随后的功能增益和功能缺失实验表明,JPT2的过表达促进了HTR-8/SVneo滋养层细胞的增殖、迁移、侵袭、球形形成及其与子宫内膜基质细胞的附着,而JPT2的敲除则抑制了这些生物学行为。此外,JPT2还能加速瘦素受体(LEPR)的转录,并以转录因子AP-2γ依赖的方式激活信号转导和激活转录3(STAT3)信号。此外,沉默 LEPR 可消除 JPT2 的作用:我们的研究结果表明,在 SCH 大鼠流产胎盘中下调的 JPT2 作为转录辅助因子,通过调节 LEPR/STAT3 轴促进滋养层细胞的增殖、迁移、侵袭、球形体形成和附着。这表明,JPT2的低表达可能是导致SCH患者流产的原因之一。
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来源期刊
Journal of Endocrinological Investigation
Journal of Endocrinological Investigation ENDOCRINOLOGY & METABOLISM-
CiteScore
8.10
自引率
7.40%
发文量
242
期刊介绍: The Journal of Endocrinological Investigation is a well-established, e-only endocrine journal founded 36 years ago in 1978. It is the official journal of the Italian Society of Endocrinology (SIE), established in 1964. Other Italian societies in the endocrinology and metabolism field are affiliated to the journal: Italian Society of Andrology and Sexual Medicine, Italian Society of Obesity, Italian Society of Pediatric Endocrinology and Diabetology, Clinical Endocrinologists’ Association, Thyroid Association, Endocrine Surgical Units Association, Italian Society of Pharmacology.
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