Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays

Fukushima, Noriyoshi; Sato, Norihiro; Prasad, Nagarajan Rajendra; Leach, Steven D.; Hruban, Ralph H.; Goggins, Michael

doi:10.1038/sj.onc.1208117

Cited by 99 publications

(70 citation statements)

References 52 publications

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“…It has been shown that Notch-1 is activated as a direct consequence of EGFR activation in pancreatic cancer (5). It has been documented that the Notch genes and Notch target genes, including Hes-1 and cyclin D1, are overexpressed in human pancreatic cancer (5,25,26). Initial studies were done to examine the relative levels of EGFR in nine pancreatic cancer cell lines, such as BxPC-3, HPAC, PANC-1, AsPC-1, COLO-357, CAPAN1, CAPAN2, L3.6pl, and MIAPaCa, by Western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Invasion in Pancreatic Cancer

Wang¹,

Sengupta

Banerjee³

et al. 2006

Cancer Research

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The epidermal growth factor receptor (EGFR) signaling network plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting EGFR would be extremely valuable for pancreatic cancer therapy. EGFR-related protein (ERRP), a recently identified pan-erbB inhibitor, has been shown to inhibit growth and induce apoptosis of pancreatic cancer cells in vitro and tumor growth in a xenograft model. However, the precise molecular mechanism(s) by which ERRP exerts its antitumor activity remains unclear. The current investigation was undertaken to delineate the tumor growth inhibitory mechanism(s) of ERRP in pancreatic cancer cells. Using multiple molecular assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis, gene transfection, real-time reverse transcription-PCR, Western blotting, invasion, and electrophoretic mobility shift assay for measuring DNA-binding activity of nuclear factor-KB (NF-KB), we found that ERRP caused marked inhibition of pancreatic cancer cell growth. This was accompanied by increased apoptosis and concomitant attenuation of Notch-1 and NF-KB and down-regulation of NF-KB downstream genes, such as matrix metalloproteinase-9 and vascular endothelial growth factor, resulting in the inhibition of pancreatic cancer cell invasion through the Matrigel. We also found that downregulation of Notch-1 by small interfering RNA before ERRP treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the ERRP-mediated inactivation of EGFR, Notch-1, NF-KB, and its downstream target genes contributed to the inhibition of cell growth and invasion. We conclude that ERRP could be an effective agent for inhibiting tumor growth and invasion for the treatment of pancreatic cancer. (Cancer Res 2006; 66(15): 7653-60)

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Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Invasion in Pancreatic Cancer

Wang¹,

Sengupta

Banerjee³

et al. 2006

Cancer Research

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“…Fresh frozen tissues of IPMNs and normal pancreata were obtained from surgical specimens resected at The Johns Hopkins Medical Institutions and stored at À70jC with the approval of the Institutional Committee for Clinical Investigation. All frozen sections were carefully evaluated with H&E staining, and IPMNs (intraductal component) and normal pancreatic ducts were selectively microdissected either manually or by laser capture microdissection (Pixcell II LCM system, Arcturus Engineering, Inc., Mountain View, CA), as described previously (21,23). Pancreatic and biliary cancer xenografts were established in nude mice from surgically resected primary pancreatic carcinomas, and 23 xenografts were used in this study.…”

Section: Methodsmentioning

confidence: 99%

“…For these IPMNs, the intraductal component was selectively microdissected manually for gene expression analysis so that we were able to obtain a high neoplastic cellularity of f80% to 90% (21). The quality of laser capture microdissected normal ductal epithelial cells was carefully evaluated using the gene expression of a panel of epithelial as well as acinar markers (23). Of 22,283 probe sets featured on the Affymetrix HG-U133A chip, 642 transcripts were found to have greatest variation (SD/mean > 1) across all the 17 samples.…”

Section: Identification Of Genes Significantly Underexpressed In Ipmnsmentioning

confidence: 99%

Epigenetic Down-Regulation of CDKN1C/p57KIP2 in Pancreatic Ductal Neoplasms Identified by Gene Expression Profiling

Sato

Matsubayashi

Abe

et al. 2005

Clinical Cancer Research

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103

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Purpose: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is an increasingly identified precursor to infiltrating ductal adenocarcinoma. Although our knowledge of the clinical and pathologic features of IPMNs is increasing, the molecular mechanisms underlying these neoplasms remain poorly understood. Experimental Designs: To provide further insight into the molecular pathobiology of IPMNs, global expression profiling was done to determine genes that are inactivated/down-regulated in IPMNs using oligonucleotide microarrays (Affymetrix). Results: In total, 300 unique transcripts (217 known genes) were identified as highly underexpressed in 12 IPMNs (<10-fold lower and P < 0.05) compared with five normal pancreatic ductal epithelium samples obtained by laser capture microdissection. The differential expression of a selection of genes was confirmed using reverse-transcription PCR. One of the genes underexpressed at both the transcriptional and protein level in a significant proportion of IPMNs was the cyclin-dependent kinase inhibitor, CDKN1C/p57KIP2. CDKN1C expression was also decreased in many pancreatic cancer cell lines and was restored following treatment with a DNA methylation inhibitor (5-aza-2V -deoxycitidine) or, more potently, with a histone deacetylase inhibitor (trichostatin A). Partial methylation of the CDKN1C promoter CpG island was found in most, but not all, pancreatic cancer cell lines with reduced CDKN1C expression, and was also detectable in IPMNs. Furthermore, a subset of pancreatic cancers showed complete hypomethylation of LIT1, an imprinting control region important for the regulation of CDKN1C expression. Complete hypomethylation in these cancers was the result of deletion of the methylated LIT1 allele at 11p15.5 rather than loss of imprinting. Conclusions: These findings suggest that CDKN1C is commonly down-regulated in pancreatic ductal neoplasms through a combination of promoter hypermethylation, histone deacetylation, and loss of the maternal allele expressing CDKN1C. Intraductal papillary mucinous neoplasm (IPMN) is anincreasingly recognized noninvasive cystic neoplasm of the pancreas that is characterized by unique clinical, pathologic, and molecular features (1 -8). Although most IPMNs are slowgrowing and less aggressive compared with conventional ductal adenocarcinoma, early and accurate diagnosis of IPMNs is important because an associated infiltrating adenocarcinoma is frequently identified in the pancreas affected by IPMNs, suggesting that IPMNs evolve into invasive ductal adenocarcinomas (2, 7, 9 -11). Recent evidence also suggests that many individuals with an inherited susceptibility to develop pancreatic ductal adenocarcinoma may initially develop IPMNs prior to developing pancreatic adenocarcinoma. In this regard, two recently completed studies have undertaken the screening of asymptomatic individuals at high risk for developing pancreatic neoplasia using endoscopic ultrasound and computed tomography scanning of the pancreas. The first study identified ...

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“…al Fukushima et al, 2004). Such data, when considered collectively, suggest a causative link between Aurora-A and c-Myc in tumorigenesis.…”

Section: Introductionmentioning

confidence: 94%

Suppression of Aurora-A oncogenic potential by c-Myc downregulation

Yang

Zhou

et al. 2010

Exp Mol Med

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Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays

Cited by 99 publications

References 52 publications

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Invasion in Pancreatic Cancer

Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Invasion in Pancreatic Cancer

Epigenetic Down-Regulation of CDKN1C/p57KIP2 in Pancreatic Ductal Neoplasms Identified by Gene Expression Profiling

Suppression of Aurora-A oncogenic potential by c-Myc downregulation

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