Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas
Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas
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DOI：
10.1016/s0002-9440(10)64681-0
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发表时间：
2001-06-01
影响因子：
6
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Kurose, K;Zhou, XP;Eng, C
PTEN（MMAC 1/TEP 1）是位于染色体10q23.3亚带的抑癌基因，在多种人类癌症中发生突变和/或缺失。编码双特异性磷酸酶的PTEN的种系突变涉及至少两种表现出一些临床重叠的错构瘤肿瘤综合征，Cowden综合征和Bannayan-Riley-Ruvalcaba综合征。在几个卵巢癌系列中，标记物nanking和PTEN内的杂合性丢失（洛）频率接近30 - 50%，而体细胞基因内突变频率<10%。在这项研究中，我们筛选原发性卵巢腺癌的洛多态性标记内和侧翼的PTEN基因和基因内突变的PTEN基因，并比较它们与PTEN表达使用免疫组化。此外，我们试图通过免疫组织化学检测假定的PTEN下游靶点，如P-Akt，p27和cyclin D1的表达。64例中29例（45%）在10 q23处观察到洛缺失。在117例样本中，7例（6%）患者中发现6例体细胞基因内突变，1例生殖系突变和1例新的多态性。49例卵巢癌组织中，13例（27%）PTEN表达阴性，25例（51%）表达减弱，其余（22%）表达阳性。在44例评估10 q23洛和PTEN免疫染色的信息性肿瘤中，10 q23洛与染色减少或缺失之间存在关联（P = 0.0317）。值得注意的是，有5个（11%）既没有突变也没有缺失的肿瘤没有表现出PTEN表达，10个（25%）没有突变或缺失但PTEN表达降低。在49例可用于免疫组化的肿瘤中，28例（57%）显示P-Akt阳性染色，24例（49%）p27染色减少，35例（79%）细胞周期蛋白D1过表达。P-Akt表达与PTEN表达呈负相关（P = 0.0083）。这些数据表明，几种机制，等位基因丢失，基因内突变，或表观遗传沉默，破坏PTEN，都有助于上皮卵巢癌的发生，表观遗传沉默是一个重要的机制。Akt通路显著参与，但显然不是在所有情况下。令人惊讶的是，尽管体外证明p27和细胞周期蛋白D1位于PTEN和Akt的下游，但p27和细胞周期蛋白D1表达与PTEN或P-Akt状态之间没有相关性。因此，在体内，虽然PTEN和Akt在卵巢癌的发生中起着重要作用，但p27和cyclin D1可能不是主要的下游靶点。或者，这些观察结果也可能表明，途径涉及以外的Akt，p27和细胞周期蛋白D1的Lie下游的PTEN在卵巢癌的发生中发挥作用。
PTEN (MMAC1/TEP1), a tumor suppressor gene on chromosome subband 10q23.3, is variably mutated and/or deleted in a variety of human cancers. Germline mutations in PTEN, which encode a dual-specificity phosphatase, have been implicated in at least two hamartoma tumor syndromes that exhibit some clinical overlap, Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Among several series of ovarian cancers, the frequency of loss of heterozygosity (LOH) of markers nanking and within PTEN, is similar to 30 to 50%, and the somatic intragenic PTEN mutation frequency is < 10%. In this study, we screened primary adenocarcinomas of the ovary for LOH of polymorphic markers within and flanking the PTEN gene and for intragenic mutations of the PTEN gene and compared them to PTEN expression using immunohistochemistry. Furthermore, we sought to detect the expression of the presumed downstream targets of PTEN, such as P-Akt, p27, and cyclin D1 by immunohistochemistry. LOH at 10q23 was observed in 29 of 64 (45%) cases. Of the 117 samples, 6 somatic intragenic PTEN mutations, 1 germline mutation, and 1 novel polymorphism were found in 7 (6%) patients. Immunostaining of 49 ovarian cancer samples revealed that 13 (27%) were PTEN immunostain-negative, 25 (51%) had reduced staining, and the rest (22%) were PTEN expression-positive. Among the 44 informative tumors assessed for 10q23 LOH and PTEN immunostaining, there was an association between 10q23 LOH and decreased or absent staining (P = 0.0317). Of note, there were five (11%) tumors with neither mutation nor deletion that exhibited no PTEN expression and 10 (25%) others without mutation or deletion but had decreased PTEN expression. Among the 49 tumors available for immunohistochemistry, 28 (57%) showed P-Akt-positive staining, 24 (49%) had decreased p27 staining, and cyclin D1 was overexpressed in 35 (79%) cases. In general, P-Akt expression was inversely correlated with PTEN expression (P = 0.0083). These data suggest that disruption of PTEN by several mechanisms, allelic loss, intragenic mutation, or epigenetic silencing, all contribute to epithelial ovarian carcinogenesis, and that epigenetic silencing is a significant mechanism. The Akt pathway is prominently involved, but clearly not in all cases. Surprisingly, despite in vitro demonstration that p27 and cyclin D1 lies downstream of PTEN and Akt, there was no correlation between p27 and cyclin D1 expression and PTEN or P-Akt status. Thus, in vivo, although PTEN and Akt play a prominent role in ovarian carcinogenesis, p27 and cyclin D1 might not be the primary downstream targets. Alternatively, these observations could also suggest that pathways involving other than Akt, p27 and cyclin D1 that Lie downstream of PTEN play roles in ovarian carcinogenesis.