The Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA.
The Division of Gastroenterology, Lankenau Medical Center, Wynnewood, USA.
Dig Dis Sci. 2021 Apr;66(4):1195-1211. doi: 10.1007/s10620-020-06319-x. Epub 2020 May 15.
Chemopreventive effects of zinc for esophageal cancer have been well documented in animal models. This prospective study explores if a similar, potentially chemopreventive action can be seen in Barrett's esophagus (BE) in humans.
To determine if molecular evidence can be obtained potentially indicating zinc's chemopreventive action in Barrett's metaplasia.
Patients with a prior BE diagnosis were placed on oral zinc gluconate (14 days of 26.4 mg zinc BID) or a sodium gluconate placebo, prior to their surveillance endoscopy procedure. Biopsies of Barrett's mucosa were then obtained for miRNA and mRNA microarrays, or protein analyses.
Zinc-induced mRNA changes were observed for a large number of transcripts. These included downregulation of transcripts encoding proinflammatory proteins (IL32, IL1β, IL15, IL7R, IL2R, IL15R, IL3R), upregulation of anti-inflammatory mediators (IL1RA), downregulation of transcripts mediating epithelial-to-mesenchymal transition (EMT) (LIF, MYB, LYN, MTA1, SRC, SNAIL1, and TWIST1), and upregulation of transcripts that oppose EMT (BMP7, MTSS1, TRIB3, GRHL1). miRNA arrays showed significant upregulation of seven miRs with tumor suppressor activity (-125b-5P, -132-3P, -548z, -551a, -504, -518, and -34a-5P). Of proteins analyzed by Western blot, increased expression of the pro-apoptotic protein, BAX, and the tight junctional protein, CLAUDIN-7, along with decreased expression of BCL-2 and VEGF-R2 were noteworthy.
When these mRNA, miRNA, and protein molecular data are considered collectively, a cancer chemopreventive action by zinc in Barrett's metaplasia may be possible for this precancerous esophageal tissue. These results and the extensive prior animal model studies argue for a future prospective clinical trial for this safe, easily-administered, and inexpensive micronutrient, that could determine if a chemopreventive action truly exists.
锌在动物模型中对食管癌的化学预防作用已得到充分证实。本前瞻性研究旨在探讨类似的、潜在的化学预防作用是否能在人类 Barrett 食管 (BE) 中看到。
确定是否可以获得分子证据，表明锌在 Barrett 化生中具有化学预防作用。
在进行监测内窥镜检查程序之前，将先前诊断为 BE 的患者给予口服葡萄糖酸锌 (14 天，每天两次，每次 26.4 毫克锌) 或葡萄糖酸钠安慰剂。然后从 Barrett 黏膜获得活检，进行 miRNA 和 mRNA 微阵列或蛋白质分析。
锌诱导的 mRNA 变化在大量转录物中观察到。这些包括编码促炎蛋白的转录物下调 (IL32、IL1β、IL15、IL7R、IL2R、IL15R、IL3R)，抗炎介质上调 (IL1RA)，介导上皮间质转化 (EMT) 的转录物下调 (LIF、MYB、LYN、MTA1、SRC、SNAIL1 和 TWIST1)，以及反对 EMT 的转录物上调 (BMP7、MTSS1、TRIB3、GRHL1)。miRNA 阵列显示具有肿瘤抑制活性的七种 miR 显著上调 (-125b-5P、-132-3P、-548z、-551a、-504、-518 和 -34a-5P)。通过 Western blot 分析的蛋白质中，促凋亡蛋白 BAX 和紧密连接蛋白 CLUDIN-7 的表达增加，而 BCL-2 和 VEGF-R2 的表达减少值得注意。
当综合考虑这些 mRNA、miRNA 和蛋白质分子数据时，锌在 Barrett 化生中的化学预防作用可能对这种癌前食管组织有效。这些结果和广泛的先前动物模型研究为这种安全、易于管理且廉价的微量营养素的未来前瞻性临床试验提供了依据，可以确定是否存在化学预防作用。
