Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma

Reiser–Erkan, Carolin; Erkan, Mert; Zheng, Pan; Bekasi, Sandor; Giese, Nathalia A.; Streit, Sylvia; Michalski, Christoph; Friess, Helmut; Kleeff, Jörg

doi:10.4161/cbt.7.9.6418

Cited by 98 publications

(75 citation statements)

References 27 publications

(49 reference statements)

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“…In agreement with these data are the up-regulation of cMYC and VEGF in human cord blood CD34 ϩ cells by STAT5 in an HIF2␣-dependent manner. Although so far PIM1 has only been described as a HIF1␣ target gene, 36,37 we do find that PIM1 is also up-regulated in STAT5-transduced HSCs. In addition to the growthpromoting activity of these genes, it has been suggested that HIF2␣ might contribute to the growth of tumor cells via activation of EGFR and IGFR1 tyrosine kinases.…”

Section: Discussionmentioning

confidence: 44%

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Fátrai

Wierenga

Daenen

et al. 2011

Blood

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The transcription factor signal transducer and activator of transcription 5 (STAT5) fulfills essential roles in selfrenewal in mouse and human hematopoietic stem cells (HSCs), and its persistent activation contributes to leukemic transformation, although little molecular insight into the underlying mechanisms has been obtained. In the present study, we show that STAT5 can impose longterm expansion exclusively on human HSCs, not on progenitors. This was asso-

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Section: Discussionmentioning

confidence: 44%

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Fátrai

Wierenga

Daenen

et al. 2011

Blood

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“…105 In addition, increased PIM1 expression was proposed to be a prognostic marker for pancreatic ductal adenocarcinoma. 106 Tumor-associated hypoxia seems to increase PIM1 expression and to support chemoresistance shown in several solid cancer cell lines. 107 These observations suggest that targeting of PIM1 might be beneficial in combination with chemotherapeutics for the therapy of solid cancers.…”

Section: Solid Tumorsmentioning

confidence: 98%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

327

413

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The online version of this article has a Supplementary Appendix.The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. Haematologica 2010;95:1004-1015. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACTin blast crisis. 6 Abundant levels of PIM1 were found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFNγ, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels ( Figure 1). Other studies have shown that PIM1 kinase is significantly protected from proteasomal degradation by heat shock proteins (Hsp70, Hsp90). 8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression. 10,11 Germline inactivation of the PIM1 gene was associated with a mild phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1 -/-mice showed erythrocytic microcytosis and PIM1-/-B cells and bone marrow-derived mast c...

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“…Immunohistochemistry was performed using the Dako Envision System, as published previously (22). Briefly, consecutive paraffin-embedded tissue sections (3 μm thick) were deparaffinized and rehydrated using routine methods.…”

Section: Reagentsmentioning

confidence: 99%

“…Semiquantitative analysis was performed as published previously (22). Scores were given separately for the stained area and for the intensity of staining.…”

Section: Semi-quantitative Analysis Of Grp94 Expression In Tissuesmentioning

confidence: 99%

Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

Zheng

Erkan²,

Streit³

et al. 2009

Int J Oncol

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Abstract. As a molecular chaperone, GRP94 is the most abundant glycoprotein in the endoplasmic reticulum, playing an important role in maintaining cellular homeostasis. Here, we investigated the expression and the role of GRP94 in regulating cell growth and apoptosis in pancreatic cancer cells. GRP94 mRNA levels were analyzed by QRT-PCR. Immunohistochemistry was performed to localize GRP94 in tissues of the normal pancreas (n=20), chronic pancreatitis (n=20) and pancreatic ductal adenocarcinoma (n=44). Silencing of GRP94 expression was carried out by transfection with specific siRNA oligonucleotides. Apoptosis was induced by treatment with actinomycin D. Compared to normal pancreatic tissues, median mRNA levels of GRP94 were 1.5-and 3.7-fold (p<0.05) lower in chronic pancreatitis and pancreatic cancer tissues, respectively. GRP94 protein was strongly expressed in normal acinar cells and moderately expressed in normal ductal cells. GRP94 expression was lost in 48% of the cancer cases. Moderate or strong staining in cancer cells was observed in 32 and 20% of pancreatic cancer tissues, respectively. Silencing GRP94 by siRNA increased apoptosis of pancreatic cancer cells in vitro. Patients with higher than the median expression have a tendency for a worsened survival. When the small number of patients with the highest expression (n=3) were compared with the rest of the group (n=41), the survival difference was significantly worse (5 vs. 18 months, respectively, p=0.006). Downregulation of GRP94 decreases apoptosis resistance in pancreatic cancer cells. Clinically, patients with high GRP94 expression show a tendency for a worsened survival.

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Hypoxia-inducible proto-oncogene Pim-1 is a prognostic marker in pancreatic ductal adenocarcinoma

Cited by 98 publications

References 27 publications

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

Identification of HIF2α as an important STAT5 target gene in human hematopoietic stem cells

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

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