染料木黄酮通过抑制H3K27三甲基化诱导人类乳腺癌症内分泌抵抗。

IF 4.1 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Endocrine-related cancer Pub Date : 2023-01-24 Print Date: 2023-02-01 DOI:10.1530/ERC-22-0191
Chunyan Hu, Manli Wang, Miao Hu, Shanshan Ma, Bingmo Yang, Wei Xiao, Qian Zhou, Ming Zhou, Zhong Li
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引用次数: 0

摘要

染料木黄酮(GE)是饮食中最重要的植物雌激素,已知其作为雌激素受体α的部分激动剂,对乳腺癌症细胞系的生长具有增殖作用。最近的研究报告称,长期服用低剂量的GE会导致MCF-7肿瘤的激素非依赖性生长表型,HER2增加。在人类癌症中,HER2的过度表达与内分泌抵抗有关,但长期低水平的GE-诱导的HER2表达是否是内分泌抵抗的原因仍有待确定。GE的短期和长期治疗可能对HER2的表达产生不同的影响。我们发现,在雌激素受体阳性的乳腺癌细胞中,低剂量的GE具有雌激素样作用,并在短期暴露后抑制HER2的表达。然而,与短期暴露相比,长期暴露诱导HER2表达增加,从而导致内分泌抵抗。在长期低水平暴露期间,ERK1/2磷酸化EZH2在Ser21的连续激活导致赖氨酸27三甲基化的减少。随着H3K27me3水平的降低,白细胞介素-6(IL-6)和IL-8的表达增加,HER2水平逐渐升高,形成ERK1/2/EZS2/IL-6和IL-8/HER2的反馈回路。我们确定了一种新的途径,EZH2磷酸化有助于长期低水平GE诱导的HER2过表达,并为长期低水平的GE诱导的获得性内分泌抵抗提供了新的见解。对于癌症患者,长期低水平使用大豆补充剂有潜在的健康风险,当患者接受他莫昔芬治疗时,监测GE的饮食暴露是可取的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genistein induces endocrine resistance in human breast cancer by suppressing H3K27 trimethylation.

Genistein (GE), the most important phytoestrogen in diet, is known to behave as a partial agonist of estrogen receptor α and shows a proliferative effect on the growth of breast cancer cell lines. Recent research has reported that long-term consumption of low doses of GE results in hormone-independent growth phenotypes of MCF-7 tumors, with increased HER2. Overexpression of HER2 has been associated with endocrine resistance in human breast cancer, but whether long-term low-level GE-induced HER2 expression is the cause of endocrine resistance remains to be determined. Short-term and long-term treatments with GE may have different effects on HER2 expression. We found that low doses of GE had estrogen-like effects and inhibited HER2 expression after short-term exposure in estrogen receptor-positive breast cancers cells. However, in contrast to short-term exposure, long-term exposure induced an increase in HER2 expression, which led to endocrine resistance. During long-term low-level exposure, the continuous activation of ERK1/2-phosphorylated EZH2 at Ser21 resulted in a decrease of lysine 27 trimethylation. As H3K27me3 levels decreased, the expression of interleukin-6 (IL-6) and IL-8 increased, and HER2 levels gradually increased, forming a feedback loop of ERK1/2/EZH2/IL-6 and IL-8/HER2. We identified a novel pathway by which EZH2 phosphorylation contributed to long-term low-level GE-induced HER2 overexpression and provided new insight for long-term low-level GE-induced acquired endocrine resistance. For breast cancer patients, long-term low-level use of soy supplements has potential health risks, and monitoring dietary exposure to GE is advisable when patients are treated with tamoxifen.

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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.
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