miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal.
miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal.
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DOI：
10.1007/s10142-016-0512-1
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发表时间：
2017-05
影响因子：
2.9
通讯作者：
Schmittgen TD
中科院分区：
文献类型：
--
作者：
Azevedo-Pouly AC;Sutaria DS;Jiang J;Elgamal OA;Amari F;Allard D;Grippo PJ;Coppola V;Schmittgen TD
携带G12D激活Kras突变的小鼠是胰腺癌(PDAC)研究领域中研究最多的模型之一。MiRNAs在PDAC患者和小鼠模型的PDAC中差异表达。为了更好地了解Kras激活对miRNA表达的影响，我们从对照组、年轻和老年P48+/CRE、LSL-KrasG12D以及PDX-1-CRE；LSL-KrasG12D小鼠的胰腺中分离出629个miRNAs的表达谱。与野生型小鼠相比，100个差异表达的miRNAs在晚期疾病(OLD)P48+/CRE；LSL-KrasG12D中的表达增加。有趣的是，位于11qA3.3~30kBP区域的miR-216a、miR-216b和miR-217三个miRNAs在这些小鼠中的表达随着年龄(和表型严重程度)的增加而降低。在另一个腺泡特异性ELA-KrasG12D小鼠模型中也检测到了miR-216/-217的表达，并且也被下调。由于miR-216/-217在人PDAC和靶KRAS中腺泡丰富、减少，我们推测它们可能维持腺泡分化或代表肿瘤抑制的miRNAs。为了验证这一假设，我们在小鼠的生殖系中删除了11qA3.3的27.9kBP区域，其中包含miR-216/-217宿主基因。我们报告说，该簇的生殖系缺失在小鼠中是胚胎致死的。我们估计致命性发生在E9.5之后不久。对miR-216B和miR-217在杂合子动物中表达的定量聚合酶链式反应分析表明，杂合子动物的miR-216B和miR-217的表达没有差异，提示通过某种类型的代偿机制实现了单效率。我们报告了在KrasG12D转基因小鼠中miRNA的差异表达，并报告了小鼠生殖系中miR-216/-217宿主基因缺失的致死性。
Mice harboring a G12D activating Kras mutation are among the most heavily studied models in the field of pancreatic adenocarcinoma (PDAC) research. miRNAs are differentially expressed in PDAC from patients and mouse models of PDAC. To better understand the relationship that Kras activation has on miRNA expression, we profiled the expression of 629 miRNAs in RNA isolated from the pancreas of control, young, and old P48+/Cre;LSL-KRASG12D as well as PDX-1-Cre;LSL-KRASG12D mice. One hundred of the differentially expressed miRNAs had increased expression in the advanced disease (old) P48+/Cre;LSL-KRASG12D compared to wild-type mice. Interestingly, the expression of three miRNAs, miR-216a, miR-216b, and miR-217, located within a ~30-kbp region on 11qA3.3, decreased with age (and phenotype severity) in these mice. miR-216/-217 expression was also evaluated in another acinar-specific ELa-KrasG12D mouse model and was downregulated as well. As miR-216/-217 are acinar enriched, reduced in human PDAC and target KRAS, we hypothesized that they may maintain acinar differentiation or represent tumor suppressive miRNAs. To test this hypothesis, we deleted a 27.9-kbp region of 11qA3.3 containing the miR-216/-217 host gene in the mouse's germ line. We report that germ line deletion of this cluster is embryonic lethal in the mouse. We estimate that lethality occurs shortly after E9.5. qPCR analysis of the miR-216b and miR-217 expression in the heterozygous animals showed no difference in expression, suggesting haplosufficiency by some type of compensatory mechanism. We present the differential miRNA expression in KrasG12D transgenic mice and report lethality from deletion of the miR-216/-217 host gene in the mouse's germ line.