Changes in mitochondrial stability during the progression of the Barrett’s esophagus disease sequence

Abstract

BackgroundBarrett’s esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett’s esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett’s disease progression is under studied.MethodsUsing an in-vitro model representing the Barrett’s esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles.ResultsBarrett’s metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett’s disease sequence in-vitro. Using patient in-vivo samples, Barrett’s metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett’s metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett’s metaplastic tissue compared with matched normal squamous epithelium.ConclusionsWe have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett’s disease sequence.

Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma

“…Degradation of mitochondrial cristae and mitochondrial dysfunction appear to be hallmarks of nonacid pepsin‐mediated injury that are potentially mediated through pepsin‐suppression of Bcl‐2 family proteins involved in maintaining cristae structure and mitochondrial homeostasis . Mitochondrial dysfunction is an indicator of mitochondrial DNA damage by reactive oxygen species, which is a common occurrence during chronic inflammation and is implicated in the etiology of metaplastic and neoplastic progression including BE …”

“…20 Mitochondrial dysfunction is an indicator of mitochondrial DNA damage by reactive oxygen species, which is a common occurrence during chronic inflammation and is implicated in the etiology of metaplastic and neoplastic progression including BE. 44,45 GERD is a chronic condition often persisting for years, during which the esophagus is bathed in up to 3 mg/mL pepsin >73 times per day. Exposure of the esophageal mucosa is not limited to the duration of the reflux event.…”

Analysis of Differentially Expressed Genes in a Chinese Cohort of Esophageal Squamous Cell Carcinoma

“…Esophageal cancer (EC) ranks as the sixth most common cancer worldwide and is the fourth most common cause of cancer deaths in China [1,2]. Nearly 500,000 new cases of EC are diagnosed every year and the often late discovery of this cancer is associated with poor prognosis with only a 5-year survival rate of ~14% [3,4].…”

Establishing Minimal Clinically Important Differences for the Quality of Life Instrument in Patients with Esophageal Cancer QLICP-ES (V2.0) Based on Anchor-Based and Distribution-Based Methods

“…Esophageal cancer (ES) is the sixth most common cancer in the world and the fourth most common cause of cancer deaths in China. Nearly half a million new ES cases are diagnosed each year [1,2]. In China, the incidence of esophageal cancer ranks the sixth among malignant tumors, and the incidence of male cancer is higher than female cancer, and the incidence of rural cancer is higher than urban cancer [3].…”