GPNMB 促进肿瘤生长,是淋巴管瘤病的生物标记物

IF 4.1 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Endocrine-related cancer Pub Date : 2024-04-01 DOI:10.1530/erc-23-0312
Erin Gibbons, Manisha Taya, Huixing Wu, Samia H Lopa, Joel Moss, Elizabeth P. Henske, Francis X. Mccormack, Stephen R Hammes
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引用次数: 0

摘要

淋巴管瘤病(LAM)是一种罕见的进行性囊性肺病,几乎只影响女性患者。囊肿是由两个结节性硬化症(TSC)基因之一发生突变的平滑肌瘤引起的肺部破坏区域。此外,生物标记物不足也阻碍了对疾病进展的监测。因此,我们需要新的治疗方案和生物标志物。LAM细胞表达黑色素细胞标志物,包括糖蛋白非转移性黑色素瘤蛋白B(GPNMB)。GPNMB在LAM中的功能目前尚不清楚;然而,GPNMB在肿瘤细胞和良性细胞上的独特细胞表面表达使其成为潜在的治疗靶点,其细胞外外延的持续释放表明其有可能成为血清生物标志物。在这里,我们证实 GPNMB 的表达依赖于 mTORC1 信号转导,并且 GPNMB 在体外调节 TSC2 基因缺失肿瘤细胞的侵袭。此外,我们还证明了 GPNMB 可促进体内 TSC2 基因缺失异种移植瘤的生长,而异种移植瘤的生长需要外结构域的释放。我们还证明,GPNMB的外结构域会被蛋白酶ADAM10和17从TSC2-null细胞的细胞表面释放出来,并确定了GPNMB上的蛋白酶靶序列。最后,我们证明了在 LAM 患者血清中,GPNMB 外结构域的含量高于健康对照组,而且外结构域的含量会随着 mTORC1 的抑制而降低,从而使其成为一种潜在的 LAM 生物标志物。
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GPNMB promotes tumor growth and is a biomarker for lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in-vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in-vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

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来源期刊
Endocrine-related cancer
Endocrine-related cancer 医学-内分泌学与代谢
CiteScore
7.80
自引率
2.60%
发文量
138
审稿时长
6-12 weeks
期刊介绍: Endocrine-Related Cancer is an official flagship journal of the Society for Endocrinology and is endorsed by the European Society of Endocrinology, the United Kingdom and Ireland Neuroendocrine Society, and the Japanese Hormones and Cancer Society. Endocrine-Related Cancer provides a unique international forum for the publication of high quality original articles describing novel, cutting edge basic laboratory, translational and clinical investigations of human health and disease focusing on endocrine neoplasias and hormone-dependent cancers; and for the publication of authoritative review articles in these topics. Endocrine neoplasias include adrenal cortex, breast, multiple endocrine neoplasia, neuroendocrine tumours, ovary, prostate, paraganglioma, parathyroid, pheochromocytoma pituitary, testes, thyroid and hormone-dependent cancers. Neoplasias affecting metabolism and energy production such as bladder, bone, kidney, lung, and head and neck, are also considered.
期刊最新文献
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