High-Resolution Genomic and Expression Profiling Reveals 105 Putative Amplification Target Genes in Pancreatic Cancer

Mahlamäki, Eija; Kauraniemi, Päivikki; Monni, Outi; Wolf, Maija; Hautaniemi, Sampsa; Kallioniemi, Anne

doi:10.1593/neo.04130

Cited by 107 publications

(82 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Amplification and overexpression of AKT2 in 19q13.2 is well established in pancreatic cancer (Cheng et al, 1996). In the present investigation, we identified 12 additional amplified and overexpressed genes in this region, including PAK4 (Mahlama¨ki et al, 2004), involved in the reorganization of the cytoskeleton and in inducing antiapoptotic effects. Thus, by systematically searching for overexpressed genes within precisely mapped amplicons in these cell lines, it became evident that several genes in each amplified segment showed significant transcriptional response to the corresponding copy number increase.…”

Section: Gene/est Band Mbmentioning

confidence: 65%

Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications

Heidenblad

Lindgren

Veltman³

et al. 2005

Oncogene

View full text Add to dashboard Cite

DNA copy number alterations are believed to play a major role in the development and progression of human neoplasms. Although most of these genomic imbalances have been associated with dysregulation of individual genes, their large-scale transcriptional consequences remain unclear. Pancreatic carcinomas frequently display gene copy number variation of entire chromosomes as well as of chromosomal subregions. These changes range from homozygous deletions to high-level amplifications and are believed to constitute key genetic alterations in the cellular transformation of this tumor type. To investigate the transcriptional consequences of the most drastic genomic changes, that is, genomic amplifications, and to analyse the genome-wide transcriptional effects of DNA copy number changes, we performed expression profiling of 29 pancreatic carcinoma cell lines and compared the results with matching genomic profiling data. We show that a strong association between DNA copy numbers and mRNA expression levels is present in pancreatic cancer, and demonstrate that as much as 60% of the genes within highly amplified genomic regions display associated overexpression. Consequently, we identified 67 recurrently overexpressed genes located in seven precisely mapped commonly amplified regions. The presented findings indicate that more than one putative target gene may be of importance in most pancreatic cancer amplicons.

show abstract

Section: Gene/est Band Mbmentioning

confidence: 65%

Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications

Heidenblad

Lindgren

Veltman³

et al. 2005

Oncogene

View full text Add to dashboard Cite

show abstract

“…The other members of the PAK family have been identified as regulators of tumor formation in the breast [10] , colon [11] , ovary [12] , pancreas [13] , and prostate [14] . Although the role of PAK5 in cancer progression has not been fully investigated, two recent reports suggest that PAK5 is overexpressed in colorectal cancer and can promote cancer-cell invasion [15,16] .…”

Section: Wwwchinapharcom Fang Zp Et Almentioning

confidence: 99%

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

Fang¹,

Jiang

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC). Methods: HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL-7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA-transfected HepG2 cells was evaluated in BALB/cA nude mice. Results: The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G 1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCCrelated genes Cyclin D1 and beta-catenin. Conclusion: PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC.

show abstract

“…However, with the application of global analysis methods to human cancers, the finding of recurrent allelic losses or copy number gains of specific loci indicates additional genetic targets remain to be found. [3][4][5][6][7] For example, novel candidate oncogenes include SMURF1 on 7q21, FGFR1 on 8p12, BIRC2 and BIRC3 on 11q22 and PAK4 on 19q13 while novel candidate tumor suppressor genes include TUSC3 on 8p22 and FEZ1 on 8p23. [4][5][6][7][8] The objective of this study was to identify novel targets of genetic alteration that contribute to pancreatic cancer development or progression.…”

Section: Introductionmentioning

confidence: 99%

Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma

Fu¹,

Luo²,

Lakkur³

et al. 2008

Cancer Biology & Therapy

View full text Add to dashboard Cite

Multiple genetic alterations are well recognized as contributing to pancreatic carcinogenesis, although the finding of recurrent copy number changes indicates additional targets remain to be found. The objective of this study was to identify novel targets of genetic alteration that contribute to pancreatic cancer development or progression. We used Representational Oligonucleotide Microarray Analysis (ROMA) to identify copy number changes in pancreatic cancer xenografts, and validated these findings using FISH, quantitative PCR, Western blotting and immunohistochemical labeling. With this approach, we identified a 0.36-Mb amplification at 18q11.2 containing two known genes, GATA-6 and cTAGE1. Using a cutoff value of 3.0 fold compared to haploid controls, copy number gain or amplification was confirmed in 4 of 42 (9.5%) pancreatic carcinomas analyzed. Combined genetic and transcriptional analyses showed consistent overexpression of GATA-6 in all carcinomas with 18q11.2 gain, as well as in the majority of pancreatic cancers examined (17 of 30 cancers, 56.7%) that did not have gain of this region. By contrast, overexpression of cTAGE1 was rare in these same cancers suggesting GATA-6 is the true target of this copy number increase. GATA-6 mRNA overexpression corresponded to robust nuclear protein expression in cancer cell lines and resected tissues consistent with its role as a transcription factor. Intense nuclear labeling was significantly increased in PanIN-3 lesions and infiltrating carcinomas compared to normal duct epithelium (p < 0.000001 and p < 0.003, respectively). Forced overexpression of GATA6 in MiaPaca2 cells resulted in increased proliferation and growth in soft-agar. Gain and overexpression of the developmentrelated transcription factor GATA-6 may play an important and hitherto unrecognized role in pancreatic carcinogenesis.

show abstract

High-Resolution Genomic and Expression Profiling Reveals 105 Putative Amplification Target Genes in Pancreatic Cancer

Cited by 107 publications

References 39 publications

Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications

Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma

Contact Info

Product

Resources

About