Shellman Z, Aldhahrani A, Verdon B, Mather M, Paleri V, Wilson J, Pearson J, Ward C, Powell J
Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne, UK.
Clin Otolaryngol. 2017 Oct;42(5):969-973. doi: 10.1111/coa.12822. Epub 2017 Jan 18.
Gastro-oesophageal reflux disease is thought to be a risk factor for head and neck malignancies. Bile acids are one of the principle components of gastric refluxate and have previously been implicated in the development of oesophageal and bowel malignancies. There is clear evidence that bile acids reflux into the laryngopharynx. Despite this, the carcinogenic properties of bile acids in this area are yet to be fully identified. We therefore investigated the potential role of bile acids in pharyngeal malignancy, through the highly conserved process of epithelial-mesenchymal transition (EMT). EMT occurs in invasion and metastasis and is a central process in the development of epithelial carcinoma.
Translational research study.
Human hypopharyngeal squamous carcinoma FaDu cells were challenged with primary (cholic or chenodeoxycholic) and secondary (deoxycholic or lithocholic) bile acids. EMT-relevant proteins TGF-β1 and MMP-9 were measured in the cell culture supernates at 48 h via ELISA. Cell viability was confirmed >95% via CellTiter-Blue assay.
Significantly greater concentrations of TGF-β1 were measured in the culture supernates of cells treated with cholic acid, deoxycholic acid and chenodeoxycholic acid. MMP-9 levels were increased in deoxycholic acid and lithocolic acid stimulations when compared to control (P < 0.05).
This is the first demonstration that bile acids induce TGF-β1 and MMP-9 in pharyngeal cells. TGF-β1 is considered a master switch for EMT, while MMP-9 is a part of the EMT proteome which degrades basement membranes. This implies a potential role for bile acids in pharyngeal carcinogenesis through the mechanism of EMT and suggests potential novel therapeutic targets.
胃食管反流病被认为是头颈部恶性肿瘤的一个危险因素。胆汁酸是胃反流物的主要成分之一，此前已被认为与食管和肠道恶性肿瘤的发生有关。有明确证据表明胆汁酸会反流至喉咽。尽管如此，胆汁酸在该区域的致癌特性尚未完全明确。因此，我们通过上皮-间质转化（EMT）这一高度保守的过程，研究了胆汁酸在咽部恶性肿瘤中的潜在作用。EMT发生于侵袭和转移过程中，是上皮癌发展的核心过程。
转化研究。
用初级胆汁酸（胆酸或鹅去氧胆酸）和次级胆汁酸（脱氧胆酸或石胆酸）处理人下咽鳞状细胞癌FaDu细胞。48小时后，通过酶联免疫吸附测定法（ELISA）检测细胞培养上清液中与EMT相关的蛋白转化生长因子-β1（TGF-β1）和基质金属蛋白酶-9（MMP-9）。通过细胞活力检测试剂盒（CellTiter-Blue法）确认细胞活力>95%。
在用胆酸、脱氧胆酸和鹅去氧胆酸处理的细胞培养上清液中，检测到的TGF-β1浓度显著更高。与对照组相比，脱氧胆酸和石胆酸刺激下MMP-9水平升高（P<0.05）。
这是首次证明胆汁酸可诱导咽部细胞产生TGF-β1和MMP-9。TGF-β1被认为是EMT的主开关，而MMP-9是EMT蛋白质组的一部分，可降解基底膜。这意味着胆汁酸可能通过EMT机制在咽部致癌过程中发挥作用，并提示了潜在新的治疗靶点。
