Harris Joseph C, Clarke Philip A, Awan Altaf, Jankowski Janusz, Watson Susan A
Academic Unit of Cancer Studies, West Block, Queen's Medical Center, University Hospital, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
Cancer Res. 2004 Mar 15;64(6):1915-9. doi: 10.1158/0008-5472.can-03-2713.
Mechanisms by which premalignant Barrett's metaplasia (BM) progresses to esophageal adenocarcinoma are currently being sought. This study investigated the role played by the polypeptide hormone gastrin, specifically its antiapoptotic effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell lines with low basal levels of activated PKB/Akt, phosphorylation could be induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt were linked to endogenous gastrin expression and were reduced by treatment with a cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a constitutively active splice variant of the CCK-2R additionally increased basal activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may aid progression of BM through amplification of antiapoptotic pathways. Evidence for this proposal was provided through the observed specific up-regulation of PKB/Akt in BM samples.
目前正在探寻癌前巴雷特化生（BM）进展为食管腺癌的机制。本研究调查了多肽激素胃泌素所起的作用，具体而言，是其通过激活蛋白激酶B/Akt（PKB/Akt）产生的抗凋亡作用。在基础水平的活化PKB/Akt较低的食管细胞系中，外源性酰胺化胃泌素可诱导磷酸化。高水平的基础活化PKB/Akt与内源性胃泌素表达相关，并通过用2型胆囊收缩素受体（CCK-2R）拮抗剂处理而降低。CCK-2R的组成型活性剪接变体的表达还增加了PKB/Akt的基础活化。有人提出，胃泌素通过CCK-2R亚型以自分泌和内分泌方式发挥作用，可能会激活PKB/Akt，并且随着BM样本中胃泌素和CCK-2R亚型的表达增加，胃泌素可能通过放大抗凋亡途径来促进BM的进展。通过在BM样本中观察到PKB/Akt的特异性上调，为这一观点提供了证据。
