Prkar1a gene knockout in the pancreas leads to neuroendocrine tumorigenesis.
Prkar1a gene knockout in the pancreas leads to neuroendocrine tumorigenesis.
复制标题
胰腺中Prkar1a基因敲除会导致神经内分泌肿瘤发生。
DOI：
10.1530/erc-16-0443
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发表时间：
2017-01
影响因子：
3.9
通讯作者：
Stratakis CA
中科院分区：
文献类型：
--
作者：
Saloustros E;Salpea P;Starost M;Liu S;Faucz FR;London E;Szarek E;Song WJ;Hussain M;Stratakis CA
Carney综合征（CNC）是一种与多种肿瘤相关的罕见疾病，包括胰腺肿瘤的易感性;最常见的原因是PRKAR 1A基因失活，PRKAR 1A基因是环AMP（cAMP）依赖性激酶（PKA）的调节因子。我们在表达pdx 1的小鼠细胞中创建了prkar 1a的无效等位基因（Δ-Prkar 1a）。小鼠在4-5月龄时发生内分泌或混合内分泌/腺泡细胞癌，100%转移。间质浸润和局部淋巴结转移证明了肿瘤的恶性行为。在组织学上，大多数肿瘤表现为胰岛细胞瘤中所见的类器官模式。从生物化学角度来看，这些病变表现出高PKA活性，正如人们对删除prkar 1a所预期的那样。这些肿瘤细胞的主要神经内分泌性质证实了免疫组织化学染色和电子显微镜，后者揭示了特征性颗粒。尽管Δ-Prkar 1a小鼠在禁食过夜后发生低血糖，但血浆中的胰岛素和胰高血糖素水平正常。最常见的肽（胰岛素，C-肽，胰高血糖素，胃泌素，生长抑素）的免疫组化染色呈阴性，表明这些肿瘤是无功能的。我们推测，最近发现的多能pdx 1 +/胰岛素-细胞在成人胰腺，引起内分泌，或混合内分泌/腺泡胰腺恶性肿瘤后增加PKA活性。该小鼠模型支持prkar 1a作为胰腺中的肿瘤抑制基因的作用，并指出PKA通路作为这些病变的可能治疗靶点。
Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by inactivation of the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). We created null alleles of prkar1a in mouse cells expressing pdx1 (Δ-Prkar1a). Mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4–5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes. Histologically, most tumors exhibited an organoid pattern as seen in the islet-cell tumors. Biochemically, the lesions exhibited high PKA activity, as one would expect from deleting prkar1a. The primary neuroendocrine nature of these tumor cells was confirmed by immunohistochemical staining and electron microscopy, the latter revealing the characteristic granules. Although the Δ-Prkar1a mice developed hypoglycemia after overnight fasting, insulin and glucagon levels in the plasma were normal. Negative immunohistochemical staining for the most common produced peptides (insulin, c-peptide, glucagon, gastrin, somatostatin) suggested that these tumors were non-functioning. We hypothesize that the recently identified multipotent pdx1+/insulin- cell in adult pancreas, gives rise to endocrine, or mixed endocrine/acinar pancreatic malignancies upon increasing PKA activity. This mouse model supports the role of prkar1a as a tumor suppressor gene in the pancreas and points to the PKA pathway as a possible therapeutic target for these lesions.