Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development

Abstract

Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 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 adenocarcinoma (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.apoptosis ͉ pancreatic cancer ͉ ponasterone A ͉ tumor suppressor ͉ micro RNA

MicroRNA-155 Expression has Prognostic Value in Patients with Non-small Cell Lung Cancer and Digestive System Carcinomas

“…Oncogenic properties of miR-155 are attributed to its anti-apoptotic function through a blockade of caspase-3 activity or suppressing proapoptotic genes such as TP53BP1 (Gironella et al, 2007;Ovcharenko et al, 2007), and promote cell proliferation by downregulating the SOCS1 gene (Jiang et al, 2010), or activate AKT signaling via down-regulation of tumor suppressors including PTEN, PDCD4 and SHIP1 (Yamanaka et al, 2009). Besides, miR-155 is regulated by the transforming growth factor-beta (TGF-β)/Smad4 pathway and plays a role in cell invasion by targeting RhoA (Kong et al, 2008).…”

MiR‐155 targets TP53INP1 to regulate liver cancer stem cell acquisition and self‐renewal

“…It has been reported that TP53INP1 is a cancer suppressor, which is associated with an oncogenic microRNA miR-155 [22,23]. And repressing TP53INP1 significantly enhanced the ability of the CD133 À cells to initiate spheroid formation [24], but whether silencing TP53INP1 could increase the population of CD133 + cells is unknown.…”

TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death

“…7,8 Our laboratory demonstrated that TP53INP1 is a tumor suppressor on the basis of the following observations: (i) TP53INP1 deficient mice present with an increased susceptibility to tumor development; (ii) TP53INP1 is lost at very early stages of pancreatic carcinogenesis through a mechanism involving the oncogenic miR-155 microRNA and (iii) when TP53INP1 expression is restored in pancreatic cells, it suppresses xenograft growth by increasing apoptotic cell death through a caspase-dependent mechanism. 3,9,10 More recently, in an attempt to decipher the molecular mechanism by which TP53INP1 induces cell death, we found that it interacts with a family of proteins involved in autophagy. Such interaction had already been reported for the TP53INP1 paralog TP53INP2 (also known as DOR) that shows 30% of amino-acid identity with TP53INP1.…”

“…One of the p53 target genes is TP53INP1 (tumor protein 53-induced nuclear protein 1). [3][4][5][6] p53-dependent expression of TP53INP1 is triggered in response to several stress agents such as mutagens, ethanol, heat shock or conditions promoting reactive oxygen species formation (i.e., exposure to UV light or g-irradiation). 4,6 TP53INP1 interacts with kinases, HIPK2 and PKCd, which in turn phosphorylate p53 creating a positive feedback loop between p53 and TP53INP1.…”