Yale Cancer Center

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Noxious Combination of Tobacco Smoke Nitrosamines with Bile, Deoxycholic Acid, Promotes Hypopharyngeal Squamous Cell Carcinoma, via NFκB, In Vivo
In vivo chronic exposure (12–14 weeks) of murine (C57Bl/6J) hypopharyngeal epithelium to tobacco smoke components (TSC) [N-nitrosamines; 4-(N-Methyl-N-Nitrosamino)-1-(3-pyridyl)-1-butanone (0.2 mmol/L), N-nitrosodiethylamine (0.004 mmol/L)], as the sole drinking fluid 5 days per week, along with topically applied (two times/day) bile [deoxycholic acid (0.28 mmol/L)], can accelerate TSC-induced neoplastic process, causing invasive carcinoma, enhancing NFκB activation and inducing a profound overexpression of Il6, Tnf, Stat3, Egfr, Wnt5a, composing an aggressive phenotype. Early assessment of bile components in refluxate of tobacco users can prevent the chronic silent progression of upper aerodigestive tract carcinogenesis. This in vivo model indicates that bile reflux might have an additive effect on the tobacco-smoke N-nitrosamines effect and could be suitable for large-scale studies of diagnostic and therapeutic interventions.
Source: AACR
22 Feb 2022
News
Targeting STAT3 prevents bile reflux-induced oncogenic molecular events linked to hypopharyngeal carcinogenesis
Acidic bile induces aberrant activation of signal transducer and activator of transcription 3 (STAT3) oncogene in hypopharyngeal cells. Targeting the STAT3 pathway, by knocking down STAT3 (STAT3 siRNA) or its pharmacologic inhibition by blocking STAT3 phosphorylation (Nifuroxazide) or dimerization (SI3‐201; STA‐21), significantly suppressed acidic bile‐induced STAT3 activation and its transcriptional activity, Bcl‐2 overexpression, transcriptional activation of IL6, TNF‐α, BCL2, EGFR, STAT3, RELA(p65), REL and WNT5A, and cell survival. Our novel findings document the important role of STAT3 in bile reflux‐related molecular oncogenic events, which can be dramatically prevented by STAT3 silencing. STA‐21, SI3‐201, or Nifuroxazide effectively inhibited STAT3 and cancer‐related inflammatory phenotype, encouraging their single or combined application in preventive or therapeutic strategies of bile reflux‐related hypopharyngeal carcinogenesis.
Source: Wiley
30 Nov 2021
News
Bile reflux and hypopharyngeal cancer (Review).
Bile acids are frequently present in the gastroesophageal refluxate and their effect has been associated with inflammatory and neoplastic changes in the upper aerodigestive tract. Recent in vitro and in vivo studies have provided direct evidence of the role of acidic bile refluxate in hypopharyngeal carcinogenesis and documented the crucial role of NF‑κB as a key mediator of early oncogenic molecular events in this process and also suggested a contribution of STAT3. Acidic bile can cause premalignant changes and invasive squamous cell cancer in the affected hypopharynx accompanied by DNA damage, elevated p53 expression, and oncogenic mRNA and microRNA alterations, previously linked to head and neck cancer. The most important findings that strongly support bile reflux as an independent risk factor for hypopharyngeal cancer are presented in the current review and the underlying mechanisms are provided.
Source: SPANDISOS PUBLICATIONS
23 Sep 2021
News
Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells
Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. To explore the pepsin effect on a specific oncogenic pathway and the importance of pH in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells to pepsin (1 mg/mL), and showed that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on cells, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1β, TNF-α, RELA(p65), BCL-2, IL6, and STAT3. We provide new evidence of the pepsin effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in hypopharyngeal cells, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease.
Source: MDPI
21 Apr 2021
News
The Yale Larynx Lab chosen as cover of Oncotarget, Vol 11, Issue 35
The cover for issue 35 of Oncotarget features Figure 4, "The in vivo pre- or post- topical application of BAY 11-7082 prevents the acidic bile-induced deregulation of cancer-related miRNA markers in 10-day exposed murine HM," by Vageli, et. al.
1 Sep 2020