MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus.
MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus.
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DOI：
10.1038/s41419-018-0628-4
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发表时间：
2018-05-29
影响因子：
9
通讯作者：
Bushell MD
中科院分区：
文献类型：
--
作者：
Godfrey JD;Morton JP;Wilczynska A;Sansom OJ;Bushell MD
胰腺导管腺癌（PDAC）是一种极具侵袭性且预后不良的疾病。这部分是由于很大比例的pdac携带TP53突变，这赋予了促进转移的功能获得特性。有证据表明，microRNAs （miRNAs）可能在TP53的功能获得突变和转移中发挥作用，但这在PDAC中尚未得到充分的探讨。在这里，我们着手鉴定在转移性PDAC中特异性失调的mirna。为了实现这一目标，我们利用已建立的PDAC小鼠模型来分析表达转移诱导突变体p53R172H的原发肿瘤中miRNA的表达，并将其与两种携带突变的对照模型进行比较，这两种突变促进肿瘤进展，但不诱导转移。我们发现，在表达突变p53R172H的小鼠PDAC肿瘤组织、来自具有相同突变的小鼠的原代细胞系以及异位表达同源人类突变p53R175H的TP53零细胞中，miRNAs的一个亚群出现了失调。具体而言，miR-142-3p在所有这些实验模型中均下调。我们发现DNA甲基转移酶1 （Dnmt1）在表达p53R172H的肿瘤组织和细胞系中上调。抑制或缺失Dnmt1可恢复miR-142-3p的表达。过表达miR-142-3p会减弱表达p53r172h的肿瘤细胞的侵袭能力。已知MiR-142-3p失调与癌症进展、转移有关，并且在PDAC患者中miRNA下调。在这里，我们将TP53功能获得突变与Dnmt1表达和miR-142-3p表达联系起来。此外，我们显示了这些基因的表达与患者生存之间的相关性，表明它们可能有潜力成为治疗靶点。
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognostic implications. This is partly due to a large proportion of PDACs carrying mutations in TP53, which impart gain-of-function characteristics that promote metastasis. There is evidence that microRNAs (miRNAs) may play a role in both gain-of-function TP53 mutations and metastasis, but this has not been fully explored in PDAC. Here we set out to identify miRNAs which are specifically dysregulated in metastatic PDAC. To achieve this, we utilised established mouse models of PDAC to profile miRNA expression in primary tumours expressing the metastasis-inducing mutant p53R172H and compared these to two control models carrying mutations, which promote tumour progression but do not induce metastasis. We show that a subset of miRNAs are dysregulated in mouse PDAC tumour tissues expressing mutant p53R172H, primary cell lines derived from mice with the same mutations and in TP53 null cells with ectopic expression of the orthologous human mutation, p53R175H. Specifically, miR-142-3p is downregulated in all of these experimental models. We found that DNA methyltransferase 1 (Dnmt1) is upregulated in tumour tissue and cell lines, which express p53R172H. Inhibition or depletion of Dnmt1 restores miR-142-3p expression. Overexpression of miR-142-3p attenuates the invasive capacity of p53R172H-expressing tumour cells. MiR-142-3p dysregulation is known to be associated with cancer progression, metastasis and the miRNA is downregulated in patients with PDAC. Here we link TP53 gain-of-function mutations to Dnmt1 expression and in turn miR-142-3p expression. Additionally, we show a correlation between expression of these genes and patient survival, suggesting that they may have potential to be therapeutic targets.
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影响因子：
56.9
作者：
CHO, YJ;GORINA, S;PAVLETICH, NP
通讯作者：
PAVLETICH, NP
DOI：
10.1046/j.1432-1033.2002.02972.x
发表时间：
2002-06-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Kishikawa, S;Murata, T;Yokoyama, KK
通讯作者：
Yokoyama, KK
影响因子：
8
作者：
Garibaldi, F.;Falcone, E.;Gurtner, A.
通讯作者：
Gurtner, A.
影响因子：
4.7
作者：
Chik, Flora;Szyf, Moshe
通讯作者：
Szyf, Moshe
影响因子：
14.9
作者：
Chung IF;Chang SJ;Chen CY;Liu SH;Li CY;Chan CH;Shih CC;Cheng WC
通讯作者：
Cheng WC