Prognostic Significance of the Immediate Early Response Gene X-1 (IEX-1) Expression in Pancreatic Cancer

Sasada, Tetsuro; Azuma, Koichi; Hirai, Tatsuya; Hashida, Hiroki; Kanai, Michiyuki; Yanagawa, Takashi; Takabayashi, Arimichi

doi:10.1245/s10434-007-9669-0

Cited by 34 publications

(29 citation statements)

References 30 publications

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“…All these observations are in agreement with the fact that, in pancreatic adenocarcinoma, Nupr1 is overexpressed (11,21) and RelB is constitutively activated (41,42). The antiapoptotic factor IER3 is overexpressed in pancreatic cancer (43), and its antiapoptotic effect was confirmed in several cancer-derived cell types (34,(44)(45)(46)(47)(48). In addition to its direct antiapoptotic effect, IER3 binds the C-terminal region of RelA/p65 and inhibits its transcriptional activity (49), suggesting that IER3 may also provide negative feedback to the NF-κB pathway in response to stress.…”

Section: Discussionsupporting

confidence: 88%

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

et al. 2012

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Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras G12D , we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras G12D -expressing pancreas. Moreover, pancreasspecific deletion of Relb in a Kras G12D background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stressrelated pathway that is required for oncogenic Kras G12D -dependent transformation of the pancreas. IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate and the lowest overall survival of all cancers (less than 3%-4% at 5 years). The incidence of PDAC almost equals its mortality rate and is increasing every year, with more than 38,000 predicted new cases in the United States and 65,000 in Europe. Surgery is the most effective treatment, but the mean life expectancy of the 15%-20% of patients who present with a resectable tumor is only 15-18 months (1). Even for patients eligible for surgery, aggressive metastasis often appears after operation, and survival of patients with metastatic disease is only 3-6 months (2). Chemotherapy and radiotherapy offer limited benefit for patients undergoing surgery in metastatic disease (3). Most strategies tested so far for the treatment of PDAC have consisted of using therapies that show some efficacy in other carcinomas, but none of them improved significantly the overall survival of PDAC patients. Hence, in order to develop new, efficient therapies against PDAC, future research must take into account PDAC specificities such as its remarkable resistance to cell stress, notably to the stress induced by chemotherapy and radiotherapy (4), and the preponderant presence of a fibrotic stroma, which favors tumor progression by creating a barrier against drug delivery and

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Section: Discussionsupporting

confidence: 88%

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

et al. 2012

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“…Our results must be discussed in comparison with a previous study by Sasada and colleagues, who studied 78 patients with PDAC and found that 53% had positive staining for IER3 in the pancreas, which correlated with a better survival time than patients with negatively stained tumors (33). In contrast, we recently reported that expression of IER3 was associated with a poor prognosis in a group of 34 patients with PDAC (6).…”

Section: G12dcontrasting

confidence: 46%

“…In myelodysplastic syndromes, IER3 expression increases gradually with disease development toward acute myeloid leukemia (23,24). Finally, IER3 appears to play distinct roles in different subsets or stages of colon cancer (30)(31)(32) as well as pancreatic cancer (6,33,34). Thus, the definitive roles of IER3 in the initiation, promotion, and/or progression of these gastrointestinal malignancies remain to be defined.…”

Section: Ier3 Supports Krasmentioning

confidence: 99%

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

García¹,

Grasso²,

López-Millán³

et al. 2014

J. Clin. Invest.

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“…IER3 protein is rapidly and transiently induced by a variety of stimuli, including ionizing radiation, inflammatory cytokines, viral infection, anti-cancer drugs and growth factors (2,3), and is associated with apoptosis and cell proliferation (3,4). As it is involved in cell growth, IER3 expression has been examined in several human tumors, including pancreatic carcinoma, ovarian carcinoma, breast cancer, and myelodysplastic syndrome (5)(6)(7)(8). However, there has been no study of IER3 expression in human lung carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

et al. 2016

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Abstract. In order to investigate the involvement of the IER3/ PP2A-B56γ/ERK-positive feedback loop, which leads to sustained phosphorylation/activation of ERK in carcinogenesis, we immunohistochemically examined the expression of IER3 and phosphorylated ERK in lung tumor tissues. IER3 was overexpressed in all cases of adenocarcinomas examined, but was not overexpressed in squamous cell carcinomas. Phosphorylated ERK (pERK) was also overexpressed in almost all adenocarcinomas. EGFR and RAS, whose gene product is located upstream of ERK, were sequenced. Activating mutation of EGFR, which is a possible cause of overexpression of IER3 and pERK, was found only in 5 adenocarcinomas (42%). No mutation of RAS was found. We further examined the sequences of all exons of B56γ gene (PPP2R5C) and IER3, but no mutation was found. Using a single nucleotide insertion in intron 1 of PPP2R5C, which was found in the process of sequencing, allelic deletion of PPP2R5C was examined. Eight cases were informative (67%), and the deletion was found in 4 of them (50%). Three cases having deletion of PPP2R5C did not have EGFR mutation. Finally, PPP2R5C deletion or EGFR mutation that could be responsible for IER3/pERK overexpression was found in at least 8 cases (67% or more). This is the first report of a high incidence of deletion of PPP2R5C in human carcinomas. IntroductionIER3 (immediate early response gene 3) was first identified in fibroblasts from mouse in 1993 (1), and human IER3, formerly referred to as the immediate early gene X-1 (IEX-1), was first identified in human squamous cell carcinomas. The human IER3 gene is located on the short arm of chromosome 6 (6p21.3) and has 2 exons. The gene encodes 156 amino acids (2). IER3 protein is rapidly and transiently induced by a variety of stimuli, including ionizing radiation, inflammatory cytokines, viral infection, anti-cancer drugs and growth factors (2,3), and is associated with apoptosis and cell proliferation (3,4). As it is involved in cell growth, IER3 expression has been examined in several human tumors, including pancreatic carcinoma, ovarian carcinoma, breast cancer, and myelodysplastic syndrome (5-8). However, there has been no study of IER3 expression in human lung carcinoma.Protein phosphatase 2A (PP2A), which consists of structural subunit A, regulatory subunits B, and catalytic subunit C, has a broad spectrum of functions due to the variety of regulatory subunits, of which there are more than 20 kinds (9). PP2A can act as a tumor suppressor (10,11). B56 regulatory subunits are involved in cell proliferation signaling (11,12). Among them, PP2A-B56γ1 dephosphorylates Thr 202 of phosphorylated extracellular signal-regulated kinase (pERK), leading to inactivation of ERK (13). Furthermore, Garcia et al (14) found that the regulation of cell growth by IER3 is mediated by ERK, which also plays a central role in regulation of a variety of cellular events, including cell proliferation, differentiation, migration, and apoptosis (15,16). IER3 regulates ERK activity through its i...

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Prognostic Significance of the Immediate Early Response Gene X-1 (IEX-1) Expression in Pancreatic Cancer

Abstract: The positive IEX-1 expression in tumor tissues may be associated with a better prognosis in pancreatic cancer. An immunohistochemical assessment of IEX-1 expression may therefore be helpful for predicting patient prognosis in this disease.

Cited by 34 publications

References 30 publications

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

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