In this study, we reported the first evidence that high expression of Bmi-1 occurred in esophageal adenocarcinoma and its precursor lesions including, low- and high-grade dysplasia, Barrett’s esophagus and columnar cell metaplasia. High Bmi-1 expression increased in intensity and percentage following the early progress of adenocarcinoma from squamous epithelium (7%), columnar cell metaplasia (22%), Barrett’s esophagus (22%), low- (45%) and high-grade dysplasia (43%) and adenocarcinoma (37%). The increase in high Bmi-1 expression was significant from squamous mucosa to columnar cell metaplasia and Barrett’s esophagus and from Barrett’s esophagus to low-grade dysplasia and esophageal adenocarcinoma. In addition, the expression level of Bmi-1 protein was significantly associated with worse histologic grade of esophageal adenocarcinoma. However, high Bmi-1 expression did not show an association with overall survival in both esophageal adenocarcinoma and squamous cell carcinoma. DNA microarray analysis detected a low percentage of Bmi-1 amplification in esophageal adenocarciinoma.
The carcinogenesis of esophageal adenocarcinoma from normal epithelium was suggested to involve a series of events that includes the reflux of gastric and duodenal contents into the esophagus leading to reflux esophagitis, followed by Barrett’s esophagus, dysplasia, and esophageal adenocarcinoma
. During these events, the accumulation of genetic and epigenetic aberrations driven by inflammation, as well as acid and bile salt stimulation, contributes to the carcinogenesis. A number of genes including apoptosis-related genes, cell cycle-related genes, tumor suppressor genes, oncogenes and growth factors, have been reported to be involved in esophageal carcinogenesis. Bmi-1 has a role in epigenetic modification as a member of the polycomb-group family, and its abnormal expression may contribute to carcinogenesis
. We found Bmi-1 present in the basal layers of normal squamous mucosa layer where the stem cells are usually located, but the percentage of expression was very low and the intensity was weak. However, the percentage and intensity of high Bmi-1 expression were significantly increased following the progression from columnar cell metaplasia to adenocarcinoma. The percentage of high expression cells were doubled in low- and high-grade dysplasia compared with to columnar cell metaplasia and Barrett’s esophagus. Also, the distribution of cells with high Bmi-1 expression was observed to have a different pattern, mostly within the base of columnar cells metaplasia compared with the full gland distribution in dysplasia and adenocarcinoma. The trend of high Bmi-1 expression suggests that Bmi-1 may play an important role in the early carcinogenesis.
From a previous study, Bmi-1 was reported to act as a stable transcriptional repressor that regulates inhibitors of p16INK4a and p19ARF
. Our DNA microarray studies lends support to a previous report that p16 and p53 play important roles in early carcinogenesis of esophageal adenocarcinoma
. The high expression of Bmi-1 in precancerous lesion implies that Bmi-1 might promote cell proliferation by suppressing p16/Rb and/or p19ARF/MDM2/p53 tumor suppressor pathway in early carcinogenesis. Therefore, further investigation is needed for the role of Bmi-1 in relation to p16, p53, and other signal pathways.
In esophageal adenocarcinoma, the amplification of Bmi-1 was very low (3%) by DNA microarray study compared with to the high expression (37%) by immunohistochemical study. From previous studies on gastric and colonic adenocarcinoma, Bmi-1 was found to upregulate both at the transcriptional and translational levels
[18, 20, 21]. We assumed that high Bmi-1 expression may be involved at the transcriptional level without significant DNA amplification, suggesting that the higher expression in esophageal adenocarcinoma is not driven by changes in the DNA copy number. In addition, the 16p segment, where Bmi-1 and several genes are located, is amplified. The worse overall survival may not be solid evidence to prove the association of Bmi-1 amplification with prognosis.
We then analyzed the association between Bmi-1 expression and clinical characteristics of the patients. The analysis revealed a significant correlation between high expression of Bmi-1 in esophageal adenocarcinoma with moderately to poorly differentiated esophageal adenocarcinoma. Unlike previous studies on gastric carcinoma
, and esophageal squamous cell carcinoma
, we observed no significant correlation between high expression of Bmi-1 and esophageal adenocarcinoma and squamous cell carcinoma with other clinicopathologic features such as age, gender, stage, metastatic lymph nodes. The difference in the correlation between Bmi-1 and clinicopathologic features may reflect the tissue and population variance of these studies. The previous studies were performed in the Chinese population.
While our study showed high Bmi-1 expression of shows slightly better but not a significant difference in prognosis in esophageal adenocarcinoma, most studies showed that high Bmi-1 expression was associated with poorer prognosis
[18–20, 24, 25, 27]. However, Pietersen et al. did report a correlation between high expression of Bmi-1 and better outcome in breast cancer patients
. The non-significant prognosis for esophageal adenocarcinoma was unexpected since other gastrointestinal carcinomas showed worse prognosis with high Bmi-1 expression. The different types of epithelium located throughout the gastrointestinal system, molecular mechanisms, and population groups may explain this discrepancy.
In esophageal squamous cell carcinoma, the data on the association between Bmi-1 expression and prognosis are limited and conflicting. Our results for esophageal squamous cell carcinoma are similar to the results from Yamada et al. where they found no association in prognosis between high expression of Bmi-1 and squamous cell carcinoma
. In contrast, two other reports found patients with higher expression of Bmi-1 had lower overall survival compared with patients with worse expression of Bmi-1