Volume 12 Issue 6 - January 29, 2010 PDF
Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in Barrett's-associated esophageal adenocarcinoma
Chia-Jui Yen1,2,*, Julie G. Izzo4, Dung-Fang Lee3, Sushovan Guha5, Yongkun Wei3, Tsung-Te Wu7, Chun-Te Chen3, Hsu-Ping Kuo3, Jung-Mao Hsu3, Hui-Lung Sun3, Chao-Kai Chou3, Navtej S. Buttar9, Kenneth K. Wang9, Peng Huang8, Jaffer Ajani6 and Mien-Chie Hung3
1Institute of Clinical Medicine; 2Department of Internal Medicine, National Cheng Kung University, Tainan, Taiwan
3Departments of Molecular and Cellular Oncology; 4Experimental Therapeutics; 5Gastrointestinal Medicine and Nutrition; 6Gastrointestinal Medical Oncology; 7Pathology; 8Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
9Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Chronic gastroesophageal reflux disease which consists of the reflux of gastric contents including bile acid and gastric acid into to the lower esophagus can lead to the inflammation of esophagus. Chronic gastroesophageal reflux disease develops the pathologic transformation of normal squamous esophagus epithelium into metaplastic intestinal, like epithelium, Barrett’s epithelium which is the high risk of developing Esophageal adenocarcinoma. Esophageal adenocarcinoma has very poor clinical outcome with a five-year survival rate <20% even among patients who received combined chemotherapy and radiotherapy. Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insight into the new therapies of esophageal adenocarcinoma. Bile acids are one of the major harmful components of refluxed gastric material and repeat of bile acid exposure can induce the esophagus inflammation. Inflammation is highly associated with the cancer development such as ulcerative colitis increasing the risk of colon cancer, chronic gastritis caused by helicobacter pylori infection increasing risk of gastric cancer and chronic hepatitis B or hepatitis C increasing the risk of hepatocellular carcinoma. During the inflammation microenvironment, the inflammation cells secrete inflammation cytokine such as TNFα which can induce the cell growth transform and angiogenesis process during cancer development and progression. Bile acids are promising candidates as esophageal carcinogens because repeated exposure to bile acidcan enhances Barrett’s esophagus transformation to esophageal adenocarcinoma.

In order to discover the signal transduction events involved in the esophageal epithelium carcinogenesis. We focus on the influence of bile acid exposure to the esophageal adenocarcinoma cells and Barrett’s esophagus cells. We found that under the stimulation of bile acid, the cellular signaling pathway IKKβ was phosphorylated then influenced the TSC1 molecule phosphorylation which exists in TSC1/TSC2 complex. The phosphorylation of TSC1 could lead to activation of mTOR protein and it’s down stream protein S6K1 was also activated. This IKKβ/ TSC1/mTOR signaling pathway activated in the Esophageal adenocarcinoma cells and Barrett’s esophagus cells increased those cell proliferation ability and soft agar coloning formation ability. The activation of pTSC1 (S511) and pS6K1 (T389) by bile acid was suppressed by the IKKβ inhibitor Bay 11-7082 and mTOR inhibitor rapamycin. (Fig 1)
Fig 1 The IKKβ/TSC1/mTOR pathway was activated in Barrett’s esophagus associated esophagus adenocarcinoma cancer cells SEG-1 and BE3. (A) The phosphorylation of pTSC1 (S511) and pS6K1 (T389) increased two to three times in SEG-1 cancer cells treated with CDCA and TDCA compared with those in untreated cells. (B) The IKKβ inhibitor Bay11-7082 blocked the bile acid stimulation effect of the IKKβ/TSC1/mTOR signaling pathway in esophagus adenocarcinoma cancer cells and the cell proliferation ability was also suppressed.

To further understand the contribution of the TSC1/mTOR pathway via IKKβ signaling in the progression of Barrett’s esophagus to esophagus adenocarcinoma, we used an orthotropic animal model. We exposed the rat’s esophagus to intestinal bile acid by surgical anastomosis of the esophagus and intestines. After several months, esophageal inflammation and tumor developed, mimicking Barrett’s esophagus and esophagus adenocarcinoma in humans. Immunohistochemical staining revealed the expression of pIKKβ (S181) and pS6K1 (T389) in inflammatory Barrett’s epithelium and in esophageal adenocarcinoma compared with normal epithelium (NE). We further evaluated a tissue microarray of 123 esophagus adenocarcinoma humans’ tissue specimens and find significant expression association with pIKKβ (S181) and pS6K1 (T389). (Fig2) (Fig3)
Fig 2 In rats, the relative expression density of pIKKβ (S181) and pS6K1 (T389) was higher in inflammatory Barrett’s epithelium (BE) and in esophageal adenocarcinoma (EAC) compared with normal esophagus squamous epithelia (NE).

Fig 3 The pIKKβ(S181) and pS6K1 (T389) protein expression in 123 EAC human specimens reveled significant correlation between pIKKβ (S181) and pS6K1 (T389) positive expression.

Our research work clearly show that bile acid can activate mTOR activity, as measured by S6K1 through IKKβ signaling, in Barrett’s esophagus and esophagus adenocarcinoma. Activation of IKKβ/mTOR pathway enhances cell growth and may initiate the development of the esophagus adenocarcinoma. How to use drug treat and prevent reflux of bile acid may become an important issue for clinician to prevent development of Barrett’s esophagus and esophagus adenocarcinoma. Furthermore, blocking IKKβ or mTOR signaling with Bay 11-7082 or rapamycin can interrupt the EAC growth and transformation. The results further suggest that behind the radiotherapy and chemotherapy treatment, the Bay 11-7082 and rapamycin may be useful as target therapy drugs in the treatment of Barrett’s esophagus associated esophagus adenocarcinoma.
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