Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development
Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development
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DOI：
10.1073/pnas.0703942104
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发表时间：
2007-10-09
影响因子：
11.1
通讯作者：
Dusetti, Nelson J.
中科院分区：
文献类型：
--
作者：
Gironella, Meritxell;Seux, Mylene;Dusetti, Nelson J.
胰腺癌是一种预后极差的疾病。肿瘤蛋白53诱导的核蛋白1（TP 53 INP 1）是一个促凋亡应激诱导的p53靶基因。在这篇文章中，我们通过免疫组化分析表明，TP 53 INP 1的表达显着减少胰腺导管腺癌（PDAC），这种减少发生在胰腺癌发展的早期。TP 53 INP 1在胰腺癌衍生细胞系MiaPaCa 2中的再表达强烈降低了其形成s.c.的能力，腹腔注射，和裸鼠胰腺内肿瘤。这种抗肿瘤能力至少部分是由于半胱天冬酶3介导的细胞凋亡的诱导。此外，用表达E1 A/ras（V12）癌蛋白的逆转录病毒转化的TP 53 INP 1（-/-）小鼠胚胎成纤维细胞（MEFs）比TP 53 INP 1（+/+）转化的MEFs或TP 53 INP 1表达恢复的TP 53 INP 1（-/-）转化的MEFs产生更大的肿瘤。最后，TP 53 INP 1的表达被致癌的微小RNA miR-155抑制，该微小RNA miR-155在PDAC细胞中过表达。TP 53 INP 1是一种以前未知的miR-155靶点，具有抗肿瘤活性。
Pancreatic cancer is a disease with an extremely poor prognosis. Tumorprotein 53-induced nuclearprotein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinorna (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1(-/-) mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras(V12) oncoproteins developed bigger tumors than TP53INP1(+/+) transformed MEFs or TP53INP1(-/-) transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.