Can Bile Acids Be an Etiological Factor for Laryngeal Carcinoma?

Tutar, Hakan; Erdamar, Husamettin; Köybaşıoğlu, Ahmet; Dinç, Aykut Erdem; Ceylan, Alper; Uslu, Sabri

doi:10.1159/000327521

Cited by 15 publications

(17 citation statements)

References 54 publications

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“…Tobacco and chronic alcohol have long been considered carcinogenic risk factors of laryngopharyngeal and hypopharyngeal cancer 2, 3. Gastroduodenal reflux disease (GDRD), a variant of gastro‐oesophageal reflux disease (GERD), has also recently been considered a risk factor that may exert independent carcinogenic potential related to chronic effects of toxic gastroduodenal fluid (GDF) on hypopharyngeal epithelial cells 4, 5, 6, 7…”

Section: Introductionmentioning

confidence: 99%

“…Although, it has been found that gastroduodenal refluxate can extend to the upper aerodigestive tract of patients,5, 6, 7 the tumorigenic effect of GDF is not yet well understood. Recent in vitro and in vivo studies have defined NF‐κB to be a possible mechanistic link between acidic bile or GDF and early pre‐neoplastic events in laryngopharyngeal mucosa 8, 9, 10.…”

Section: Introductionmentioning

confidence: 99%

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NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

Doukas¹,

Vageli²,

Sasaki³

2018

J Cellular Molecular Medi

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We previously demonstrated that acidic bile activates NF‐κB, deregulating the expression of oncogenic miRNA markers, in pre‐malignant murine laryngopharyngeal mucosa. Here, we hypothesize that the in vitro exposure of human hypopharyngeal cells to acidic bile deregulates cancer‐related miRNA markers that can be reversed by BAY 11‐7082, a pharmacologic NF‐κB inhibitor. We repetitively exposed normal human hypopharyngeal primary cells and human hypopharyngeal keratinocytes to bile fluid (400 μmol/L), at pH 4.0 and 7.0, with/without BAY 11‐7082 (20 μmol/L). We centred our study on the transcriptional activation of oncogenic miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375, miR‐451a and NF‐κB‐related genes, previously linked to acidic bile‐induced pre‐neoplastic events. Our novel findings in vitro are consistent with our hypothesis demonstrating that BAY 11‐7082 significantly reverses the acidic bile‐induced oncogenic miRNA phenotype, in normal hypopharyngeal cells. BAY 11‐7082 strongly inhibits the acidic bile‐induced up‐regulation of miR‐192 and down‐regulation of miR‐451a and significantly decreases the miR‐21/375 ratios, previously related to poor prognosis in hypopharyngeal cancer. This is the first in vitro report that NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in normal human hypopharyngeal cells, suggesting that acidic bile‐induced events are directly or indirectly dependent on NF‐κB signalling.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

Doukas¹,

Vageli²,

Sasaki³

2018

J Cellular Molecular Medi

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“…Hypopharyngeal cancer is considered one of the most aggressive forms of head and neck malignancies with poor prognosis . There is evidence that bile‐containing duodenal contents are present in aspirates of patients with gastroesophageal reflux disease (GERD) and growing epidemiologic evidence supports their involvement in laryngopharyngeal neoplasia . Covington et al purport that the prevalence of bile in GERD may be greater than is believed by previous studies .…”

Section: Introductionmentioning

confidence: 99%

Curcumin prevents the bile reflux‐induced NF‐κB‐related mRNA oncogenic phenotype, in human hypopharyngeal cells

Vageli¹,

Doukas²,

Spock³

et al. 2018

J Cellular Molecular Medi

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The presence of bile is not an uncommon finding in acidic oesophageal and extra‐oesophageal refluxate, possibly affecting the hypopharyngeal mucosa and leading to neoplastic events. We recently demonstrated that acidic bile (pH ≤ 4.0) can induce NF‐κB activation and oncogenic mRNA phenotype in normal hypopharyngeal cells and generate premalignant changes in treated hypopharyngeal mucosa. We hypothesize that curcumin, a dietary inhibitor of NF‐κB, may effectively inhibit the acidic bile‐induced cancer‐related mRNA phenotype, in treated human hypopharyngeal primary cells (HHPC), supporting its potential preventive use in vivo. Luciferase assay, immunofluorescence, Western blot, qPCR and PCR microarray analysis were used to explore the effect of curcumin in HHPC exposed to bile (400 μmol/L) at acidic and neutral pH. Curcumin successfully inhibited the acidic bile‐induced NF‐κB signalling pathway (25% of analysed genes), and overexpression of NF‐κB transcriptional factors, c‐REL, RELA(p65), anti‐apoptotic bcl‐2, oncogenic TNF‐α, EGFR, STAT3, WNT5A, ΔNp63 and cancer‐related IL‐6. Curcumin effectively reduced bile‐induced bcl‐2 overexpression at both acidic and neutral pH. Our novel findings suggest that, similar to pharmacologic NF‐κB inhibitor, BAY 11‐7082, curcumin can suppress acidic bile‐induced oncogenic mRNA phenotype in hypopharyngeal cells, encouraging its future in vivo pre‐clinical and clinical explorations in prevention of bile reflux‐related pre‐neoplastic events mediated by NF‐κB.

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“…The American Cancer Society estimates in 2015 approximately 3,400 new hypopharyngeal cancer cases, with poor prognosis. Among known risk factors, such as tobacco smoking and alcohol use, gastroduodenal reflux (GDRD), a variant of gastro-esophageal reflux disease (GERD), is also considered a potential risk factor as there is growing evidence that GDRD may have carcinogenic potential related to chronic effects of toxic gastroduodenal fluids (GDFs) on hypopharyngeal mucosa (HM) [ 1 - 3 ]. However, the precise role of GDRD in hypopharyngeal carcinogenesis and its etiopathological mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Gastro-duodenal fluid induced nuclear factor-κappaB activation and early pre-malignant alterations in murine hypopharyngeal mucosa

Vageli¹,

Prasad

Sasaki³

2016

Oncotarget

115

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We recently described the role of gastro-duodenal fluids (GDFs) in generating changes consistent with hypopharyngeal neoplasia through activation of NF-κB pathway, using an in vitro model of human hypopharyngeal normal keratinocytes. Here, we further provide evidence that gastro-duodenal reflux is a risk factor for early pre-malignant alterations in hypopharyngeal mucosa (HM) related to an activated NF-κB oncogenic pathway, using both an in vitro and a novel in vivo model of C57Bl/6J mice. Histological, immunohistochemical and automated quantitative analysis documents significant NF-κB activation and early pre-malignant alterations in HM topically exposed to GDFs, compared to acid alone and other controls. Early pre-malignant histologic lesions exhibited increased Ki67, CK14 and ΔNp63, cell proliferation markers, changes of cell adhesion molecules, E-Cadherin and β-catenin, and STAT3 activation. The in vivo effect of NF-κB activation is positively correlated with p-STAT3, Ki67, CK14 or β-catenin expression, while GDFs induce significant transcriptional activation of RELA(p65), bcl-2, TNF-α, STAT3, EGFR and wnt5A, in vivo. Our in vivo model demonstrates selectively activated NF-κB in response to topically administrated GDFs, leading to early pre-malignant events in HM.

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Can Bile Acids Be an Etiological Factor for Laryngeal Carcinoma?

Cited by 15 publications

References 54 publications

NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

Curcumin prevents the bile reflux‐induced NF‐κB‐related mRNA oncogenic phenotype, in human hypopharyngeal cells

Gastro-duodenal fluid induced nuclear factor-κappaB activation and early pre-malignant alterations in murine hypopharyngeal mucosa

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