Activation of Akt is increased in the dysplasia-carcinoma sequence in Barrett's oesophagus and contributes to increased proliferation and inhibition of apoptosis: a histopathological and functional study
Activation of Akt is increased in the dysplasia-carcinoma sequence in Barrett's oesophagus and contributes to increased proliferation and inhibition of apoptosis: a histopathological and functional study
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DOI：
10.1186/1471-2407-7-97
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发表时间：
2007-06-08
期刊：
影响因子：
3.8
通讯作者：
Wilkinson, Mark
中科院分区：
文献类型：
--
作者：
Beales, Ian L. P.;Ogunwobi, Olorunseun;Wilkinson, Mark
背景：食管腺癌的发病率在发达国家迅速增加。丝氨酸-苏氨酸蛋白激酶和原癌基因Akt已被报道在几种组织中调节增殖和凋亡，但没有关于Akt参与食管癌发生的数据。因此，我们已经研究了激活的Akt在巴雷特食管和食管腺癌和Akt激活的功能作用在vitro.Methods：总的和活性（磷酸化）Akt的表达进行了测定，在内镜活检和手术切除标本，使用免疫组化。Akt的功能影响进行了检查，使用Barrett的腺癌细胞在culture.Results：在正常鳞状食管，糜烂性食管炎和非异型增生的Barrett食管，磷酸化Akt仅限于基础1/3的粘膜。图像分析证实，与鳞状上皮相比，Akt活化在非异型增生的Barrett食管中显著增加，并且在高度异型增生和腺癌中进一步显著增加。在所有高度异型增生和腺癌的病例中，Akt在上皮的1/3腔中被激活。短暂的酸暴露和肥胖激素瘦素激活Akt，刺激增殖和抑制凋亡：酸和瘦素的组合是协同的。用LY 294002抑制Akt磷酸化增加了细胞凋亡，并阻断了酸和瘦素单独和组合的作用。Akt的激活与下游促凋亡蛋白Bad的磷酸化和失活以及Forkhead家族转录因子FOXO 1的磷酸化有关。结论：Akt在Barrett食管、高度异型增生和腺癌中存在异常激活。Akt活化促进Barrett腺癌细胞增殖并抑制凋亡，短暂酸暴露和瘦素均刺激Akt磷酸化。Akt的下游靶标包括Bad和Forkhead转录因子。Akt在肥胖和胃酸反流中的激活可能在Barrett腺癌的发病机制中很重要。
Background: The incidence of oesophageal adenocarcinoma is increasing rapidly in the developed world. The serine-threonine protein kinase and proto-oncogene Akt has been reported to regulate proliferation and apoptosis in several tissues but there are no data on the involvement of Akt in oesophageal carcinogenesis. Therefore we have examined the activation of Akt in Barrett's oesophagus and oesophageal adenocarcinoma and the functional effects of Akt activation in vitro.Methods: Expression of total and active ( phosphorylated) Akt were determined in endoscopic biopsies and surgical resection specimens using immunohistochemistry. The functional effects of Akt were examined using Barrett's adenocarcinoma cells in culture.Results: In normal squamous oesophagus, erosive oesophagitis and non-dysplastic Barrett's oesophagus, phospho-Akt was limited to the basal 1/3 of the mucosa. Image analysis confirmed that Akt activation was significantly increased in non-dysplastic Barrett's oesophagus compared to squamous epithelium and further significantly increased in high-grade dysplasia and adenocarcinoma. In all cases of high grade dysplasia and adenocarcinoma Akt was activated in the luminal 1/3 of the epithelium. Transient acid exposure and the obesity hormone leptin activated Akt, stimulated proliferation and inhibited apoptosis: the combination of acid and leptin was synergistic. Inhibition of Akt phosphorylation with LY294002 increased apoptosis and blocked the effects of acid and leptin both alone and in combination. Activation of Akt was associated with downstream phosphorylation and deactivation of the pro-apoptotic protein Bad and phosphorylation of the Forkhead family transcription factor FOXO1.Conclusion: Akt is abnormally activated in Barrett's oesophagus, high grade dysplasia and adenocarcinoma. Akt activation promotes proliferation and inhibits apoptosis in Barrett's adenocarcinoma cells and both transient acid exposure and leptin stimulate Akt phosphorylation. Downstream targets of Akt include Bad and Forkhead transcription factors. Activation of Akt in obesity and by reflux of gastric acid may be important in the pathogenesis of Barrett's adenocarcinoma.