Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer

Scholz, Arne; Heinze, Sandra; Detjen, Katharina; Peters, Michael; Welzel, Martina; Hauff, Peter; Schirner, Michael; Wiedenmann, Bertram; Rosewicz, Stefan

doi:10.1016/s0016-5085(03)01064-3

Cited by 229 publications

(204 citation statements)

References 57 publications

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“…In addition, reexpression of PDX-1 has been reported in human patients and several mouse models of pancreatic cancer (Hingorani et al 2003;Koizumi et al 2003). Moreover, activation of Stat3 has been reported in a mouse model expressing TGF-␣, human patients with pancreatic cancer, and human pancreatic carcinoma cell lines (Greten et al 2002;Scholz et al 2003). These findings, together with our data, indicate that the persistent up-regulation of PDX-1 and consequent activation of Stat3 can lead to acinar-to-ductal metaplasia.…”

Section: Pdx-1 Causes Acinoductal Metaplasia Genes and Development 1437supporting

confidence: 82%

“…To verify the molecular mechanism by which PDX-1 induces acinar-to-ductal differentiation, we investigated the expression and activation of signal transducer and activator of transcription 3 (Stat3), which has been shown to be activated in cells within ductal structures in human pancreatic cancer as well as in a mouse model (Greten et al 2002;Scholz et al 2003). Immunostaining for Stat3 phosphorylated at Tyr 705, which is responsible for Stat3 activation, revealed that a number of metaplastic cells were positive for phosphorylated Stat3 in the transgenic Ptf1a-Cre; CAG-CAT-PDX1 pancreas, whereas none of the acinar and duct cells in the control pancreas were positive for phosphorylated Stat3 (Fig.…”

Section: Pdx-1 Causes Acinoductal Metaplasia Genes and Development 1437mentioning

confidence: 99%

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Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

Miyatsuka¹,

Kaneto²,

Shiraiwa³

et al. 2006

Genes Dev.

144

136

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The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches. The transgenic pancreas was markedly small with the replacement of acinar cells by duct-like structures, accompanied by activated Stat3. Genetic ablation of Stat3 in the transgenic pancreas profoundly suppressed the metaplastic phenotype. These results provide a mechanism of pancreatic metaplasia by which persistent PDX-1 expression cell-autonomously induces acinar-to-ductal transition through Stat3 activation.Supplemental material is available at http://www.genesdev.org.

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Section: Pdx-1 Causes Acinoductal Metaplasia Genes and Development 1437supporting

confidence: 82%

Section: Pdx-1 Causes Acinoductal Metaplasia Genes and Development 1437mentioning

confidence: 99%

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

Miyatsuka¹,

Kaneto²,

Shiraiwa³

et al. 2006

Genes Dev.

144

136

View full text Add to dashboard Cite

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“…Further, Src activation is involved in several aspects of cellular transformation, including proliferation, survival, migration, and invasion (48)(49)(50). Additionally, activity of the Src-family of kinases is required for signal transducers and activators of transcription 3 and FAK phosphorylation (51), and this phosphorylation is required for the progression of the cell cycle (52,53). Furthermore, it has been reported that overexpression of FAK leads to an accelerated G 1 -S -phase transition, whereas overexpression of a dominant-negative FAK inhibits cell cycle progression at G 1 (39,40).…”

Section: Discussionmentioning

confidence: 99%

Two N-Myristoyltransferase Isozymes Play Unique Roles in Protein Myristoylation, Proliferation, and Apoptosis

Ducker

Upson

French

et al. 2005

Molecular Cancer Research

102

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N-myristoyltransferases (NMT) add myristate to the NH 2 termini of certain proteins, thereby regulating their localization and/or biological function. Using RNA interference, this study functionally characterizes the two NMT isozymes in human cells. Unique small interfering RNAs (siRNA) for each isozyme were designed and shown to decrease NMT1 or NMT2 protein levels by at least 90%. Ablation of NMT1 inhibited cell replication associated with a loss of activation of c-Src and its target FAK as well as reduction of signaling through the c-Raf/mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. Terminal deoxynucleotidyl transferase -mediated dUTP nick end labeling assays showed that depletion of either NMT isozyme induced apoptosis, with NMT2 having a 2.5-fold greater effect than NMT1. Western blot analyses revealed that loss of NMT2 shifted the expression of the BCL family of proteins toward apoptosis. Finally, intratumoral injection of siRNA for NMT1 or for both NMT1 and NMT2 inhibited tumor growth in vivo, whereas the same treatment with siRNA for NMT2 or negative control siRNA did not. Overall, the data indicate that NMT1 and NMT2 have only partially overlapping functions and that NMT1 is critical for tumor cell proliferation.

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“…STATs contribute to tumorigenesis through their intimate connection to growth factor signaling, apoptosis, and angiogenesis (Bromberg, 2002). Constitutively activated STATs are detected in a wide variety of human cancer cells, including breast, prostate, renal cell, melanoma, ovarian, lung, leukemia, lymphoma, multiple myeloma, and pancreatic cancer cells (Bowman et al, 2000;Scholz et al, 2003). In cell culture, active STAT3 is either required for transformation, enhances transformation induced by other events, or blocks apoptosis (Bromberg et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway

et al. 2005

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The Kaposi's sarcoma herpesvirus encodes a G-proteincoupled chemokine receptor termed KSHV-GPCR. Expression of this constitutively active GPCR leads to cell transformation and vascular overgrowth characteristic of Kaposi's sarcoma. Previously, we have shown that CXCR2, the closest human homolog, is similarly able to transform cells if continuously stimulated or constitutively activated by amino-acid exchange D138V of the DRY sequence. Here, we demonstrate that STAT3 activation is a prerequisite for transformation in KSHV-GPCR and CXCR2 transfected NIH 3T3 cells. In KSHV-GPCR and D138V transfected cells, STAT-3 is constitutively phosphorylated on Tyr 705 . In CXCR2 transfected NIH 3T3 cells and human microvascular endothelial cells (HMEC), which express the CXCR2 constitutively, STAT3 is phosphorylated upon stimulation with IL-8 (CXCL8). Focus formation in NIH 3T3 cells transfected with the KSHV-GPCR, CXCR2, or the D138V mutant, was blocked by the specific JAK2 inhibitor AG490. Typical functions of the CXCR2 including actin stress fiber formation, haptotaxis, and the angiogenic response in HMEC shown by tube formation in Matrigel were blocked by AG490. These data suggest that the transforming capacity and migratory responses that are involved in tumor development, metastasis, and angiogenesis in KSHV or CXCR2-expressing cells is at least partially mediated through a JAK2-STAT3 dependent pathway.

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Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer

Cited by 229 publications

References 57 publications

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation

Two N-Myristoyltransferase Isozymes Play Unique Roles in Protein Myristoylation, Proliferation, and Apoptosis

KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway

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