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Biliary reflux as a causal factor in hypopharyngeal carcinoma: New clinical evidence and implications.
- Source :
-
Cancer [Cancer] 2019 Oct 15; Vol. 125 (20), pp. 3554-3565. Date of Electronic Publication: 2019 Jul 16. - Publication Year :
- 2019
-
Abstract
- 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-κB-related messenger RNA (mRNA) and microRNA (miRNA) oncogenic phenotypes similar to those previously identified in acidic bile-exposed premalignant murine hypopharyngeal mucosa.<br />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-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.<br />Results: 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.<br />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.<br /> (© 2019 American Cancer Society.)
- Subjects :
- Aged
Animals
Bile metabolism
Bile Acids and Salts metabolism
Bile Acids and Salts toxicity
Bile Reflux complications
Bile Reflux metabolism
Bile Reflux pathology
Carcinoma, Squamous Cell complications
Carcinoma, Squamous Cell metabolism
Carcinoma, Squamous Cell pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Hypopharyngeal Neoplasms complications
Hypopharyngeal Neoplasms metabolism
Hypopharyngeal Neoplasms pathology
Male
Mice
MicroRNAs genetics
Middle Aged
Mucous Membrane drug effects
Mucous Membrane pathology
NF-kappa B genetics
RNA, Messenger genetics
Bile Reflux genetics
Carcinoma, Squamous Cell genetics
Hypopharyngeal Neoplasms genetics
Neoplasm Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0142
- Volume :
- 125
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 31310330
- Full Text :
- https://doi.org/10.1002/cncr.32369