Guo S S, Wu X, Shimoide A T, Wong J, Moatamed F, Sawicki M P
Department of Surgery, West Los Angeles VA Medical Center and the UCLA School of Medicine, Los Angeles, California 90095, USA.
J Endocrinol. 2003 Oct;179(1):73-9. doi: 10.1677/joe.0.1790073.
Pancreatic endocrine tumours (PETs) occur sporadically or are inherited as part of the multiple endocrine neoplasia type-1 syndrome. Little is known about the molecular events leading to these tumours. Cyclin D1, a key regulator of the G1/S transition of the cell cycle, is overexpressed in a variety of human cancers as well as certain endocrine tumours. We hypothesized that similar to other endocrine tumours, cyclin D1 is overexpressed in human sporadic PETs. Cyclin D1 protein overexpression was found in 20 of 31 PETs (65%) when compared with normal pancreatic tIssue. Furthermore, Northern blot analysis suggests that cyclin D1 up-regulation occurs at the post-transcriptional level in some PETs. Because the key cell growth signalling pathways p42/p44/ERK (extracellular signal-regulated kinase), p38/MAPK (mitogen-activated protein kinase), and Akt/PKB (protein kinase B) can regulate cyclin D1 protein expression in other cell types, pancreatic endocrine tumours were analysed with phospho-specific antibodies against the active forms of these proteins to elucidate a tIssue-specific regulatory mechanism of cyclin D1 in PETs. We found frequent activation of the p38/MAPK and Akt pathways, but down-regulation of the ERK pathway, in cyclin D1 overexpressing PETs. This study demonstrates that cyclin D1 overexpression is associated with human sporadic PET tumorigenesis, and suggests that this up-regulation may occur at the post-transcriptional level. These findings will direct future studies of PETs towards cell cycle dysregulation and the identification of key growth factor pathways involved in the formation of these tumours.
胰腺内分泌肿瘤（PETs）可散发性发生，或作为多发性内分泌腺瘤1型综合征的一部分而遗传。关于导致这些肿瘤的分子事件，我们知之甚少。细胞周期蛋白D1是细胞周期G1/S转换的关键调节因子，在多种人类癌症以及某些内分泌肿瘤中过表达。我们推测，与其他内分泌肿瘤类似，细胞周期蛋白D1在人类散发性PETs中也过表达。与正常胰腺组织相比，在31例PETs中有20例（65%）发现细胞周期蛋白D1蛋白过表达。此外，Northern印迹分析表明，在一些PETs中，细胞周期蛋白D1的上调发生在转录后水平。由于关键的细胞生长信号通路p42/p44/ERK（细胞外信号调节激酶）、p38/MAPK（丝裂原活化蛋白激酶）和Akt/PKB（蛋白激酶B）可调节其他细胞类型中的细胞周期蛋白D1蛋白表达，因此我们用针对这些蛋白活性形式的磷酸化特异性抗体对胰腺内分泌肿瘤进行分析，以阐明细胞周期蛋白D1在PETs中的组织特异性调节机制。我们发现在细胞周期蛋白D1过表达的PETs中，p38/MAPK和Akt通路频繁激活，但ERK通路下调。本研究表明，细胞周期蛋白D1过表达与人类散发性PETs的肿瘤发生有关，并提示这种上调可能发生在转录后水平。这些发现将指导未来对PETs的研究朝着细胞周期失调以及鉴定参与这些肿瘤形成的关键生长因子通路的方向进行。
