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Biliary reflux as a causal factor in hypopharyngeal carcinoma: New clinical evidence and implications
Author(s) -
Sasaki Clarence T.,
Doukas Sotirios G.,
Costa Jose,
Vageli Dimitra P.
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.32369
Subject(s) - medicine , downregulation and upregulation , microrna , cancer research , immunohistochemistry , carcinoma , pathology , gastroenterology , biology , gene , biochemistry
Background 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‐ κ B–related messenger RNA (mRNA) and microRNA (miRNA) oncogenic phenotypes similar to those previously identified in acidic bile–exposed premalignant murine hypopharyngeal mucosa. Methods 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‐ κ B 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 . Results Bile(+) HSCC demonstrated an intense NF‐ κ B 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. Conclusions 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.