The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
Cancer. 2019 Oct 15;125(20):3554-3565. doi: 10.1002/cncr.32369. Epub 2019 Jul 16.
Recent preclinical explorations strongly support the tumorigenic potential of bile on laryngopharyngeal mucosa. Herein, the authors describe, in bile-related human hypopharyngeal squamous cell carcinoma (HSCC), NF-κB-related messenger RNA (mRNA) and microRNA (miRNA) oncogenic phenotypes similar to those previously identified in acidic bile-exposed premalignant murine hypopharyngeal mucosa.
In this pilot study, the authors included human HSCC specimens paired with their adjacent normal tissue (ANT) derived from 3 representative patients with documented biliary laryngopharyngeal reflux (bile[+]) compared with 5 control patients without signs of bile reflux disease (bile[-]). Immunohistochemical, quantitative polymerase chain reaction, and miRNA analyses were used to detect the levels of activated NF-κB and expression levels of STAT3, EGFR, BCL2, WNT5A, IL-6, IL-1B, ΔNp63, cREL, TNF-α, TP53, NOTCH1, NOTCH2, NOTCH3, miR-21, miR-155, miR-192, miR-34a, miR-375, miR-451a, miR-489, miR-504, and miR-99a.
Bile(+) HSCC demonstrated an intense NF-κB activation accompanied by significant overexpression of RELA(p65), EGFR, STAT3, BCL-2, cREL, ΔNp63, WNT5A, IL-6, and IL1B; upregulation of oncomir miR-21; and downregulation of tumor suppressor miR-375 compared with their respective ANTs. Bile(+) HSCC demonstrated significantly higher mRNA levels of all the analyzed genes, particularly RELA(p65), IL-6, EGFR, and TNF-α compared with bile(-) tumors. The miR-21/miR-375 ratio, which previously has been linked to tumor aggressiveness, was found to be >260-fold and >30-fold higher, respectively, in bile(+) HSCCs compared with their ANTs and bile(-) tumors.
Although limitations apply to this pilot study due to the small number of patients with HSCC, the novel findings suggest that a history of bile as a component of esophageal reflux disease may represent an independent risk factor for hypopharyngeal carcinogenesis.
最近的临床前探索强烈支持胆汁对喉咽黏膜的致瘤潜能。在此，作者描述了在与胆汁相关的人类下咽鳞状细胞癌（HSCC）中，NF-κB 相关信使 RNA（mRNA）和 microRNA（miRNA）致癌表型与先前在酸性胆汁暴露的癌前鼠下咽黏膜中鉴定的表型相似。
在这项初步研究中，作者纳入了 3 例有明确胆液性喉咽反流（胆汁[+]）病史的 HSCC 标本及其相邻正常组织（ANT），与 5 例无胆汁反流病（bile[-]）迹象的对照患者进行配对。作者采用免疫组织化学、定量聚合酶链反应和 miRNA 分析来检测激活型 NF-κB 以及 STAT3、EGFR、BCL2、WNT5A、IL-6、IL-1B、ΔNp63、cREL、TNF-α、TP53、NOTCH1、NOTCH2、NOTCH3、miR-21、miR-155、miR-192、miR-34a、miR-375、miR-451a、miR-489、miR-504 和 miR-99a 的表达水平。
胆汁[+]HSCC 表现出强烈的 NF-κB 激活，同时 RELA（p65）、EGFR、STAT3、BCL-2、cREL、ΔNp63、WNT5A、IL-6 和 IL1B 的过度表达；致癌 miRNA miR-21 的上调；以及肿瘤抑制 miR-375 的下调，与各自的 ANTs 相比。与胆汁[-]肿瘤相比，胆汁[+]HSCC 中所有分析基因的 mRNA 水平均显著升高，特别是 RELA（p65）、IL-6、EGFR 和 TNF-α。miR-21/miR-375 比值先前与肿瘤侵袭性相关，在胆汁[+]HSCC 中分别比 ANTs 和胆汁[-]肿瘤高 260 倍和 30 倍以上。
尽管由于 HSCC 患者数量较少，这项初步研究存在局限性，但新发现表明，胆汁作为食管反流病的一个组成部分可能是下咽癌发生的一个独立危险因素。
