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

Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering “druggable” molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL-17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL-17 functions during this transition are currently unclear. In this study, we demonstrate that IL-17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early PanIN lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiological role for REG3β during pancreatitis and PDAC initiation.

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“…Quantification represents the average of 15-20 20× fields of view for 6 mice of each genotype as previously reported (34). …”

Section: Methodsmentioning

confidence: 99%

IL17 Functions through the Novel REG3β–JAK2–STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer

et al. 2015

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“…EGFR signaling is essential for KRas-mediated pancreatic tumor growth via Erk1/2 both in vitro and in vivo [32,74–76]. Not only has the growth and development of PDA shown to be dependent on Erk1/2, but PDA initiation mediated by PanIN development is also facilitated by this signaling pathway [77–79]. In addition to Erk1/2, downstream of KRas G12D , EGFR can also drive pancreatic epithelial cell proliferation via activation of c-MYC [80].…”

Section: Ros In Pda Progressionmentioning

confidence: 99%

Targeting reactive oxygen species in development and progression of pancreatic cancer

Durand

Störz

2016

Expert Review of Anticancer Therapy

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Introduction Pancreatic ductal adenocarcinoma (PDA) is characterized by expression of oncogenic KRas which drives all aspects of tumorigenesis. Oncogenic KRas induces the formation of reactive oxygen species (ROS) which have been implicated in initiation and progression of PDA. To facilitate tumor promoting levels and to avoid oncogene-induced senescence or cytotoxicity, ROS homeostasis in PDA cells is balanced by additional up-regulation of antioxidant systems. Areas Covered We examine the sources of ROS in PDA, the mechanisms by which ROS homeostasis is maintained, and the biological consequences of ROS in PDA. Additionally, we discuss the potential mechanisms for targeting ROS homoeostasis as a point of therapeutic intervention. An extensive review of the relevant literature as it relates to the topic was conducted using PubMed. Expert Commentary Even though oncogenic mutations in the KRAS gene have been detected in over 95% of human pancreatic adenocarcinoma, targeting its gene product, KRas, has been difficult. The dependency of PDA cells on balancing ROS homeostasis could be an angle for new prevention or treatment strategies. These include use of antioxidants to prevent formation or progression of precancerous lesions, or methods to increase ROS in tumor cells to toxic levels.

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“…This positive feedback loop may be involved in carcinogenesis of lung adenocarcinoma (35). Recently, Garcia et al (36) proposed that pERK enhanced the immediate expression of IER3 in pancreatic cancer, and they found that IER3 is prominently expressed in pancreatic ductal adenocarcinoma. IER3 expression sustains phosphorylation of ERK through PP2A.…”

Section: Discussionmentioning

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

Cited by 36 publications

References 56 publications

IL17 Functions through the Novel REG3β–JAK2–STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer

IL17 Functions through the Novel REG3β–JAK2–STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer

Targeting reactive oxygen species in development and progression of pancreatic cancer

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

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