Telomere dysfunction suppresses multiple endocrine neoplasia in mice.
Telomere dysfunction suppresses multiple endocrine neoplasia in mice.
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DOI：
10.18632/genesandcancer.31
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发表时间：
2014-09
期刊：
影响因子：
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通讯作者：
Rane SG
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文献类型：
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作者：
Lee JH;Anver M;Kost-Alimova M;Protopopov A;DePinho RA;Rane SG
多发性内分泌瘤（MEN）综合征的典型特征是肿瘤在两个或多个激素组织中发生。尽管人们对男性综合症的遗传学了解相对较好，但这些癌症的致瘤机制仍然相对不清楚。Cdk4R24C小鼠模型发展为高渗透性垂体瘤和内分泌胰腺腺瘤，因此，该模型适合深入了解MEN的机制。利用这个模型，我们提供了端粒酶在MEN发病机制中发挥重要作用的证据。我们观察到Cdk4R/R成纤维细胞的非整倍性增加，同时Cdk4R/R胰岛和胚胎成纤维细胞的端粒酶活性和端粒长度显著升高。为了更好地理解端粒酶的作用，我们产生了mTERC基因座失活的Cdk4R24C小鼠（mTERC - / - Cdk4R/R小鼠），mTERC基因座编码端粒酶的基本RNA成分。来自mTERC - / - Cdk4R/R小鼠的胚胎成纤维细胞和胰岛表现出端粒长度和增殖能力的减少。此外，mTERC−/−Cdk4R/R成纤维细胞显示出降低的转化潜能。重要的是，mTERC−/−Cdk4R/R小鼠显示出明显减少的自发肿瘤发生。引人注目的是，我们观察到mTERC - / - Cdk4R/R小鼠垂体肿瘤和内分泌胰腺腺瘤的显著抑制。端粒功能障碍抑制肿瘤的发生，增加肿瘤发展的潜伏期，而不影响已建立的肿瘤的进展。综上所述，这些结果提示端粒酶在Cdk4R24C小鼠模型的肿瘤发展中发挥重要作用，特别是在垂体和内分泌胰腺肿瘤的发生中。
Multiple endocrine neoplasia (MEN) syndrome is typified by the occurrence of tumors in two or more hormonal tissues. Whereas the genetics of MEN syndrome is relatively well understood, the tumorigenic mechanisms for these cancers remain relatively obscure. The Cdk4R24C mouse model develops highly penetrant pituitary tumors and endocrine pancreas adenomas, and, as such, this model is appropriate to gain insight into mechanisms underlying MEN. Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN. We observed increased aneuploidy in Cdk4R/R fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4R/R islets and embryonic fibroblasts. To better understand the role of telomerase, we generated Cdk4R24C mice with inactivation of the mTERC locus, which codes for the essential RNA component of the enzyme telomerase (mTERC−/− Cdk4R/R mice). Embryonic fibroblasts and islets derived from mTERC−/− Cdk4R/R mice exhibit reduced telomere length and proliferative capacity. Further, mTERC−/− Cdk4R/R fibroblasts display reduced transformation potential. Importantly, mTERC−/− Cdk4R/R mice display significantly reduced spontaneous tumorigenesis. Strikingly, we observed dramatic suppression of pituitary tumors and endocrine pancreas adenomas in mTERC−/− Cdk4R/R mice. Telomere dysfunction suppressed tumor initiation and increased latency of tumor development while not affecting the progression of established tumors. In summary, these results are suggestive of an important role for telomerase in tumor development in the Cdk4R24C mouse model, specifically in the genesis of tumors in the pituitary and the endocrine pancreas.