Ras Activity in Acinar Cells Links Chronic Pancreatitis and Pancreatic Cancer

Logsdon, Craig D.; Ji, Baoan

doi:10.1016/j.cgh.2009.07.040

Cited by 54 publications

(53 citation statements)

References 35 publications

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“…This notion differs from the previous suggestion that chronic inflammation is essential for oncogenic Ras to induce tumorigenesis (9). Rather, at sufficient levels of activity, Ras is capable of generating both inflammation and tumorigenesis (7,33). Therefore, mechanisms that increase the level of Ras activity are the key to the pathological consequences.…”

Section: Figurecontrasting

confidence: 54%

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

et al. 2012

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Genetic mutations that give rise to active mutant forms of Ras are oncogenic and found in several types of tumor. However, such mutations are not clear biomarkers for disease, since they are frequently detected in healthy individuals. Instead, it has become clear that elevated levels of Ras activity are critical for Ras-induced tumorigenesis. However, the mechanisms underlying the production of pathological levels of Ras activity are unclear. Here, we show that in the presence of oncogenic Ras, inflammatory stimuli initiate a positive feedback loop involving NF-κB that further amplifies Ras activity to pathological levels. Stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long-term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous pancreatic lesions (PanINs) in mice expressing physiological levels of oncogenic K-Ras. These effects of inflammatory stimuli were disrupted by deletion of inhibitor of NF-κB kinase 2 (IKK2) or inhibition of Cox-2. Likewise, expression of active IKK2 or Cox-2 or treatment with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic K-Ras. The data support the hypothesis that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB-mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large proportion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

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Section: Figurecontrasting

confidence: 54%

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

et al. 2012

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“…Moreover, there is a close relationship on the occurrence of genetic variation between the two entities. Some key mutations in pancreatic carcinogenesis could also be detectable in part of CP, such as p16, p53, and K-ras [34][35][36]. In our study, six cases (54.5 %) of CP demonstrated low miR-483-3p expression, with none showing strong expression.…”

Section: Discussionmentioning

confidence: 63%

Elevated miR-483-3p expression is an early event and indicates poor prognosis in pancreatic ductal adenocarcinoma

Wang

Sun

et al. 2015

Tumor Biol.

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MiR-483-3p has been reported to be widely involved in diverse human malignancies. However, the exact role of miR-483-3p remains elusive in pancreatic ductal adenocarcinoma (PDAC). The objective of this study is to determine the expression pattern and clinical implications of miR-483-3p in PDAC. MiR-483-3p levels were evaluated by locked nucleic acid-in situ hybridization (LNA-ISH) in a tissue microarray including 63 PDAC tumors and 10 normal pancreatic tissues, followed by evaluation in an independent set of 117 pairs of matched PDAC tumors and adjacent tumor-free pancreatic tissues. Expression of miR-483-3p was further evaluated in pancreatic intra-epithelial neoplasias (PanINs) and chronic pancreatitis (CP). The impact of miR-483-3p on cell proliferation, growth, and anchorage-independent colony formation was also assessed in vitro and in vivo. Microarray analysis revealed that miR-483-3p was positively stained in 61 (96.8 %) PDAC samples, but not detectable in normal pancreatic duct tissue. In the 117 PDAC samples, 100 % were miR-483-3p positive, with 55.6 % (65/117) strongly positive, compared to only 13.7 % (16/117) weakly positive in adjacent normal pancreatic duct tissues. MiR-483-3p expression was associated with tumor grading (p < 0.05) and was an independent predictor of poor overall survival in multivariate analysis (HR = 2.584; 95 % CI = 1.268-5.264). Moreover, from PanIN1 to PanIN3, the rate of strong miR-483-3p-positive staining was 0 % (0/39), 14.8 % (4/27), and 87.5 % (14/16), respectively. Six (54.5 %) CP samples were only weakly stained for miR-483-3p. Inhibition of miR-483-3p suppressed cell proliferation, growth, and colony formation in vitro and decreased tumor cell growth in nude mouse xenografts in vivo. These results suggest that aberrant miR-483-3p expression is an early event in PDAC tumorigenesis and is associated with tumor differentiation and prognosis. It also may be a potential target for PDAC molecular therapeutics.

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“…MECOM has been proposed to play an early role in pancreatic cancer, in part by stimulating the accumulation of KRAS mRNA (48). An increase of active KRAS above a threshold through induction by MECOM might alter the state of acinar differentiation and increase susceptibility to malignant transformation (99). Changes in cellular identity are often a prelude to neoplasia (100,101).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

Hoang

Hale

Azevedo-Pouly

et al. 2016

Molecular and Cellular Biology

113

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Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo. Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma. Loss of cellular identity has long been associated with tissue injury and a first step in cancer progression (for examples, see references 1 and 2). Maintenance of a specific cellular phenotype depends on the continued transcription of cell-type-specific genes, largely through open chromatin architecture (3, 4) maintained by a small group of lineage-restricted DNA-binding transcription factors (TFs) (5, 6) that establish a unique transcriptional regulatory network (7). Many physiologic or pathophysiologic perturbations can affect the differentiated state of a cell quantitatively, but fewer affect the state of differentiation qualitatively. Qualitative changes involve the acquisition of characteristics of another cell type (or types), often defined by one or a few cell-specific markers, in addition to the diminution of the original phenotype. Despite progress with cellular reprogramming (for example, see reference 8), the molecular and genetic mechanisms that maintain cellular identity within the context of adult organs remain incompletely understood. In this report, we show that inactivation of the transcriptional regulatory gene Ptf1a in adult pancreatic acinar cells has pleiotropic effects on gene expression that cause quantitative and multigene qualitative changes of acinar differentiation.The acinar cell of the pancreas has been an informative model of terminal cellular differentiation (9). Common cellular processes are greatly exaggerated in support of the prodigious synthesis, processing, storage, and exocytosis of secretory proteins. The pancreatic acinar cell has the most ribosomes (10) and the highest rate of protein synthesis (11) of any mammalian somatic cell; it synthesizes, stores, and secretes its weight in protein daily. Specialized cellular functions ...

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Ras Activity in Acinar Cells Links Chronic Pancreatitis and Pancreatic Cancer

Cited by 54 publications

References 35 publications

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

Elevated miR-483-3p expression is an early event and indicates poor prognosis in pancreatic ductal adenocarcinoma

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

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